Methods of treating hypogonadism with transnasal testosterone bio-adhesive gel formulations in male with allergic rhinitis, and methods for preventing an allergic rhinitis event

ABSTRACT

The present invention relates to methods of treating hypogonadism in a male subject through administering intranasally to the male subject an intranasal testosterone bio-adhesive gel formulation to deliver a therapeutically effective amount of testosterone. In particular, the testosterone therapy of the invention remains effective if an allergic rhinitis event occurs in the male during the treatment or when the male subject uses a topical nasal vasoconstrictor or a topical intranasal decongestant during the hypogonadism treatment. Further, the present invention relates to a method of preventing the occurrence of an allergic rhinitis event in a male, who is undergoing a hypogonadism treatment with an intranasal testosterone bio-adhesive gel. In certain embodiments, the intranasal testosterone bio-adhesive gel formulation according to the invention comprises 4.0% and 4.5% testosterone.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/275,633, filed Feb. 14, 2019, which is a continuation of U.S. patentapplication Ser. No. 16/044,903, filed Jul. 25, 2018, which is acontinuation of U.S. patent application Ser. No. 15/856,156 filed Dec.28, 2017, which is a continuation of U.S. patent application Ser. No.15/599,316, filed May 18, 2017, which is a continuation of U.S. patentapplication Ser. No. 15/284,479, filed Oct. 3, 2016, which is acontinuation of U.S. patent application Ser. No. 15/045,208, filed Feb.16, 2016, which is a continuation of U.S. patent application Ser. No.14/753,552, filed Jun. 29, 2015, which is a continuation of U.S. patentapplication Ser. No. 14/536,130, filed Nov. 7, 2014, which is acontinuation of U.S. patent application Ser. No. 14/215,882, filed Mar.17, 2014, and claims the benefit of and priority to U.S. ProvisionalPatent Application No. 61/802,297, filed Mar. 15, 2013, the contents ofwhich are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to methods of treating hypogonadism in amale subject through administering intranasally to the male subject anintranasal testosterone bio-adhesive gel formulation to deliver atherapeutically effective amount of testosterone, thereby treating thehypogonadism. In particular, the present testosterone therapy remainseffective for treating hypogonadism when an allergic rhinitis eventoccurs in the male or when the male subject uses a topical nasalvasoconstrictor or a topical intranasal decongestant during thehypogonadism treatment. Further, the present invention relates to anovel method of preventing the occurrence of an allergic rhinitis eventin a male, who is undergoing a hypogonadism treatment with an intranasaltestosterone bio-adhesive gel formulation of the present invention. Incertain embodiments, the intranasal testosterone bio-adhesive gelformulation according to the present invention comprises 4.0% and 4.5%testosterone.

BACKGROUND

Androgens are a group of C19 steroids that cause masculinization of thegenital tract and the development and maintenance of male secondary sexcharacteristics. They also contribute to muscle bulk, bone mass, libido,and sexual performance in men. Testosterone is the main androgensecreted by the Leydig cells of the testes, and its production increasesduring puberty. See. e.g., Tietz: Textbook of Clinical Chemistry andMolecular Diagnostics, 4th edition, Editors: Burtis C A, Ashwood E R,and Bruns D E (2006). Androgen deficiency is now recognized to be arelatively common condition in the aging male. See, e.g., 2. Wang C,Swerdloff R. S.: Androgen replacement therapy. Ann Med, 29: 365-370(1997); Matsumoto A. M.: Andropause: clinical implications of thedecline in serum Testosterone levels with aging in men. J Gerontol A MedSci, 57: M76-M99 (2002); and Haren Mt et al.: Andropause: aquality-of-life issue in older males. Med Clin North Am, 90: 1005-1023(2006). Testosterone hormone therapy is indicated for replacementtherapy and males having conditions associated with a deficiency orabsence of endogenous testosterone, such as to treat male hypogonadism.This may cause sexual dysfunction, muscle loss, increase in fat,infertility, decreased beard and body hair and other conditions.

Hypogonadism is defined as testosterone deficiency. Male hypogonadismmay be congenital or it may develop later in life due to, e.g., injury,trauma, surgery, infection, disease, drugs and/or aging. Generally,child-onset male hypogonadism has minimal consequences and generallyremains undiagnosed until puberty is delayed. The symptoms or signsassociated with child-onset male hypogonadism, if left untreated,include poor muscle and body hair development, including poor facial,pubic, chest and axillary hair growth, a high-pitched voice, excessivegrowth of arms and legs in relation to the trunk of the body, a smallscrotum, abnormal phallic and testicular growth, and other growthproblems, e.g., growth and maturation of the prostate and seminalvesicles. In adult-onset male hypogonadism, the symptoms may include adeficiency in spermatozoa production, osteoporosis, muscle loss oralterations in body musculature, fat distribution, fatigue and loss ofenergy, weakness, anemia, mood swings, e.g., depression and anger, adecline in cognitive skills, including memory loss and inability toconcentrate, sleep disturbances, gynecomastia, a reduction in both beardand body hair, impotence, erectile dysfunction; a decrease in ejaculatevolume, infertility, a decrease in sexual desire (loss of libido), and aregression of other secondary sexual characteristics.

Male hypogonadism is designated as either primary hypogonadism, which isdue to a disorder of the testes, or central or secondary hypogonadismthat results from a disorder in the hypothalamic-pituitary axis. Inprimary hypogonadism, there is a lack of testosterone production in thetestes because the testes do not respond to FSH and LH. As a result,elevations in both hormones, FSH and LH, are observed in primary malehypogonadism. The most common cause of primary male hypogonadism isKlinefelter's syndrome. Other congenital causes of primary gonadism mayinclude, e.g., Bilateral Congenital Anorchia, Leydig Cell Hypoplasia(Leydig Cell Aplasia), undescended testicles (Cryptorchidism), Noonansyndrome, Myotonic Dystrophy (MD) and defects in testosterone enzymaticsynthesis. Causes of adult-onset primary hypogonadism may include aging,autoimmune disorders, surgery, chemotherapy, radiation, infection,disease, surgery, alcoholism, drug therapy and recreational drug use.

In secondary or central hypogonadism, insufficient amounts of FSH and LHare produced in the hypothalamus. Genital causes of secondary or centralhypogonadism include, e.g., Kallmann syndrome, Prader-Willi syndrome(PWS), Dandy-Walker malformation, Isolated luteinizing hormone (LH)deficiency and Idiopathic hypogonadotropic hypogonadism (IHH). Causes ofadult-onset secondary or central hypogonadism may include aging,disease, infections, tumors, bleeding, nutritional deficiencies,alcoholism, cirrhosis of the liver, obesity, weight loss, Cushing'ssyndrome, hypopituitarism, hyperprolactinemia, hemochromatosis, surgery,trauma, drug therapy, and recreational drug use.

In primary male hypogonadism, the levels observed for testosterone arebelow normal but are generally above normal for FSH and LH. In secondaryor central male hypogonadism, the levels observed for testosterone, FSHand LH are below normal. Thus, diagnosis of primary or secondary malehypogonadism is typically confirmed by hormone levels and, on testing,blood levels of testosterone in both primary and secondary hypogonadismare characterized as low and should be replaced. Treatment generallyvaries with etiology, but typically includes testosterone replacementtherapy. In the United States, testosterone may be administered as anintramuscular injection, a transdermal patch or a transdermal gel. Inother countries, oral preparations of testosterone may be available.

In view of the fact that millions of men in the United States, as wellas through out the world, suffer from hypogonadism, there is a real andimmediate need for an effective and convenient medical therapy that cantreat this disorder, so that the quality of life of these individualscan be improved. One therapeutic goal of one such therapy to solve thisimmediate need might be to restore testosterone levels in men to youngadulthood levels in hopes to alleviate the symptoms generally associatedwith hypogonadism due possibly to testosterone deficiency.

SUMMARY OF THE INVENTION

The present invention offers effective methods for treating hypogonadismin a male with allergic rhinitis. In particular, the methods involvedelivering a therapeutically effective amount of testosterone to themale through an intranasal administration of an intranasal testosteronebio-adhesive gel formulation. The current testosterone therapy remainseffective if an allergic rhinitis event occurs in the male during thetreatment. In addition, any topical nasal vasoconstrictor or topicalintranasal decongestant used by the male during the hypogonadismtreatment does not interfere with the efficacy of the testosteronetherapy of the invention. Further, the present invention offersadvantageous effects in a hypogonadism treatment, including, such as,preventing occurrence of an allergic rhinitis event in a male undergoinga hypogonadism treatment with an intranasal testosterone bioadhesive gelof the invention.

The term “a therapeutically effective amount” means an amount oftestosterone sufficient to induce a therapeutic or prophylactic effectfor use in testosterone replacement or supplemental therapy to treatmale testosterone deficiency, namely, hypogonadism in males.

Thus, generally speaking, the present invention provides a novel methodfor treating hypogonadism in a male by administering intranasally to themale an intranasal testosterone bioadhesive gel formulation to deliver atherapeutically effective amount of testosterone. The hypogonadismtreatment remains effective when an allergic rhinitis event occurs inthe male during the treatment.

In another aspect, the invention provides a novel method of treatinghypogonadism in a male, who is using a topical nasal vasoconstrictor ora topical intranasal decongestant during the treatment. In particular,the method comprises administering intranasally to the male anintranasal testosterone bio-adhesive gel formulation to deliver atherapeutically effective amount of testosterone.

The present invention also provides a novel method of preventing anallergic rhinitis event in a male, especially when the male isundergoing a hypogonadism treatment. The method of the inventioncomprises administering intranasally an intranasal testosteronebioadhesive gel formulation to the male to deliver a therapeuticeffective amount of testosterone for treating hypogonadism.

The intranasal testosterone bioadhesive gel formulations used herein areformulated with testosterone in amounts of between about 4% and 8.0% byweight, and preferably between about 4.0% and about 4.5% by weight, andmore preferably about 4.0%, about 4.5% and 8.0% by weight.

In accordance with the present invention, the rates of diffusion of thetestosterone in the intranasal gel formulations of the present inventionthrough a Franz cell membrane, as contemplated by the present invention,are between about 28 and 100 slope/mgT %, and preferably about 30 and 95slope/mgT %. For those intranasal gels formulated with between about4.0% and 4.5% testosterone, the preferred rates of diffusion oftestosterone are between about 28 and 35 slope/mgT %.

The present invention is also directed to novel methods for pernasaladministration of the nasal testosterone gels. Generally speaking, thenovel methods involve depositing the intranasal testosterone gelstopically into the nasal cavity of each nostril to deliver atherapeutically effective amount of testosterone in smaller volumes overdose life for providing constant effective testosterone brain and/orblood levels for use TRT, especially for effectively treating males inneed of testosterone to treat hypogonadism.

More specifically, the present invention is directed to bioavailableintranasal testosterone gel formulations suitable for pernasaladministration to for use in TRT and to treat hypogonadal subjects. Inaccordance with the present invention, and by way of example. Thepresent invention contemplates:

Treatment with unit-dose devices pre-filled with 125 μL 4.0%testosterone gel to deliver about 5.0 mg of testosterone per nostril(intra-nasal) given, e.g., three times a day (total dose 30 mg/day);

Treatment with unit-dose devices pre-filled with about 150 μL 4.5% gelto deliver about 6.75 mg of Testosterone per nostril (intra-nasal)given, e.g., twice daily (total dose 27.0 mg/day); and/or

Treatment with unit-dose devices pre-filled with about 125 μL 4.5% gelto deliver about 5.625 mg of Testosterone per nostril (intra-nasal)given, e.g., three times a day (total dose 33.75 mg/day).

Generally speaking, the intranasal testosterone gel formulations of thepresent invention are formulated with about 4% and 4.5% testosterone byweight, and the testosterone is well absorbed when such gel formulationsare administered pernasally to hypogonadal subjects. More specifically,testosterone is rapidly absorbed following pernasal administration witha peak concentration reached within 36 minutes to 1 hour 6 minutes (meanTmax) following intra-nasal administration and maximal serumconcentration is reached after about 1-2 hours post nasaladministration. The maximum Testosterone concentration over a 24-hourinterval is observed during the first administration (0-10 hours) inapproximately 57% to 71% of the hypogonadal men while approximately 29%to 43% of the subjects had their maximum 24-h Testosterone concentrationduring subsequent administrations.

The formulations containing 4% and 4.5% testosterone by weight providesurprising properties. Importantly, the solubility of testosterone incastor oil pure is 3.6% maximum, falling to 3.36% about with 4%Labrafil. Addition of fumed silica (Aerosil, CabOsil) can increase thesolubility of testosterone in castor oil up to 4.5% even with 4.0%Labrafil. This is counter intuitive for a person skilled in the art.However, without wishing to be bound by any particular theory, it isbelieved that this increase in solubility in the presence of silica isdue, at least in part, to the fact that SiO₂ adsorbs about 10% of thetestosterone.

In accordance with the novel methods of the present invention, theintranasal testosterone gels are topically deposited on the outerexternal walls (opposite the nasal septum) inside the naval cavity ofeach nostril, preferably at about the middle to about the upper sectionof the outer external wall (opposite the nasal septum) just under thecartilage section of the outer external wall inside the naval cavity ofeach nostril. Once gel deposition is complete within each nostril of thenose, the outer nose is then gently and carefully squeezed and/or rubbedby the subject, so that the deposited gel remains in contact with themucosal membranes within the nasal cavity for sustained release of thetestosterone over dose life. Typical testosterone gel dosage amountsdeposited pernasal application is between about 50 to about 150microliters per nostril, and preferably about 125 to about 150microliters per nostril.

In carrying out the methods of the present invention, approximatelybetween about 50 microliters and about 150 microliters of an intranasaltestosterone gel of the present invention is applied to each nostril ofa subject once or twice daily or three times a day, e.g., for one, two,three, four or more consecutive weeks, or for two, three, four, five orsix consecutive days or more, or intermittently such as every other dayor once, twice or three times weekly, or on demand once or twice duringthe same day, as TRT or to treat male testosterone deficiency, includingmale hypogonadism.

In addition, the present invention contemplates testosterone gelformulations for nasal administration that are pharmaceuticallyequivalent, therapeutically equivalent, bioequivalent and/orinterchangeable, regardless of the method selected to demonstrateequivalents or bioequivalence, such as pharmacokinetic methodologies,microdialysis, in vitro and in vivo methods and/or clinical endpointsdescribed herein. Thus, the present invention contemplates testosteronegel formulations for nasal administration that are bioequivalent,pharmaceutically equivalent and/or therapeutically equivalent,especially testosterone gel formulations for nasal administration thatare 0.15% testosterone by weight of the gel formulation, 0.45%testosterone by weight of the gel formulation and 0.6% testosterone byweight of the gel formulation, when used in accordance with the therapyof the present invention to treat anorgasmia and/or HSDD by intranasaladministration. Thus, the present invention contemplates: (a)pharmaceutically equivalent testosterone gel formulations for nasaladministration which contain the same amount of testosterone in the samedosage form; (b) bioequivalent testosterone gel formulations for nasaladministration which are chemically equivalent and which, whenadministered to the same individuals in the same dosage regimens, resultin comparable bioavailabilities; (c) therapeutic equivalent testosteronegel formulations for nasal administration which, when administered tothe same individuals in the same dosage regimens, provide essentiallythe same efficacy and/or toxicity; and (d) interchangeable testosteronegel formulations for nasal administration of the present invention whichare pharmaceutically equivalent, bioequivalent and therapeuticallyequivalent.

While the intranasal testosterone gels of the present invention arepreferred pharmaceutical preparations when practicing the novel methodsof the present invention, it should be understood that the novel topicalintranasal gel formulations and methods of the present invention alsocontemplate the pernasal administration of any suitable activeingredient, either alone or in combination with testosterone or otheractive ingredients, such as neurosteroids or sexual hormones (e.g.,androgens and progestins, like testosterone, estradiol, estrogen,oestrone, progesterone, etc.), neurotransmitters, (e.g., acetylcholine,epinephrine, norepinephrine, dopamine, serotonin, melatonin, histamine,glutamate, gamma aminobutyric acid, aspartate, glycine, adenosine, ATP,GTP, oxytocin, vasopressin, endorphin, nitric oxide, pregnenolone,etc.), prostaglandin, benzodiazepines like diazepam, midazolam,lorazepam, etc., and PDEF inhibitors like sildenafil, tadalafil,vardenafil, etc., in any suitable pharmaceutical preparation, such as aliquid, cream, ointment, salve or gel. Examples of additional topicalformulations for practice in accordance with the novel methods of thepresent invention include the topical pernasal formulations disclosedin, for example, U.S. Pat. Nos. 5,578,588, 5,756,071 and 5,756,071 andU.S. Patent Publication Nos. 2005/0100564, 2007/0149454 and2009/0227550, all of which are incorporated herein by reference in theirentireties.

The present invention is also concerned with a novel titration method todetermine the appropriate daily treatment regimen, i.e., a BID or TIDtreatment regimen, to administer the intranasal gels of the presentinvention to treat hypogonadism or TRT. While the preferred treatmentregimen in accordance with the present invention for administering theintranasal testosterone gels, such as 4.0% or 4.5% TBS-1 as described inExamples 1, 2, 3, 5, 7, 8, 9 and 10 above, to treat hypogonadism or TRTis twice-daily (BID) treatment regimen, the present inventioncontemplates that certain subjects may be more effectively treated witha three-times-a-day (TID) treatment regimen. Thus, the novel titrationmethod of the present invention has been developed to determine whichsubject will require a BID or TID treatment regimen to more effectivelytreat hypogonadism or TRT when treated with the intranasal testosteronegels of the present invention.

In carrying out the novel titration method in accordance with thepresent invention, subjects will have 2 blood draws, preferably at 7 amand at 8:20 am on the test day. The day before the first blood draw, thesubject will take at 10 pm, his evening intranasal dose of TBS-1. Ontest day, the subject will take at about 8 am, his morning intranasaldose of TBS-1.

The 24-hour C_(avg) of serum total testosterone will be estimated basedon the sum of serum total testosterone levels collected at the 2sampling points: the sample collected at about 9.0 hours (at 7 am, whichis 1 hour before the morning 0800 h intranasal dose) and the samplecollected at about 10.33 hours following the last evening's intranasaldose (20 minutes after the morning 0800 h dose+/−20 minutes). Note that,the blood draw times may be changed (+/−1 hour) but the delay betweenthe last dose and the first blood draw is preferably 9 hours+/−20minutes and the delay between the next dose administered at about 10hours+/−20 minutes after the last dose and the second blood draw ispreferably +/−20 minutes.

Testosterone serum concentrations are preferably measured by a validatedmethod at a clinical laboratory and reported in ng/dL units.

The following titration criteria is preferably used:

If the sum of the serum total testosterone level values for PK samplescollected at 9.0 hours and 10.33 hours is <755 ng/dL, then the estimated24-hour C_(avg) for the male patient is <300 ng/dL

If the sum of the serum total testosterone level values for PK samplescollected at 9.0 hours and 10.33 hours is 755 ng/dL, then the estimated24-hour C_(avg) for the male patient is ≥300 ng/dL.

With respect to those subjects with an estimated serum totaltestosterone C_(avg)<300 ng/dL, i.e., those subjects who sum of theserum total testosterone level values for PK samples collected at 9.0hours and 10.33 hours is <755 ng/dL, their BID treatment regimen shouldbe titrated to a TID treatment regimen of TBS-1 to achieve a 24-hourC_(avg) of ≥300 ng/dL. The decision to titrate the subject's daily doseto TID, however, will be made by the doctor based on the criteriaspecified above.

With respect to those subjects with an estimated serum totaltestosterone C_(avg)≥300 ng/dL, i.e., those subjects who sum of theserum total testosterone level values for pK samples collected at 9.0hours and 10.33 hours is ≥755 ng/dL, their BID treatment regimen shouldremain unchanged at a BID treatment regimen of TBS-1 since their 24-hourC_(avg) is ≥300 ng/dL. The decision to titrate the subject's daily doseto TID or remain at BID, however, will be made by the doctor based onthe criteria specified above.

It should be understood that, while it is preferred to draw blood from asubject to test the subject's serum total testosterone level values forpK samples at 9 hours and at 10.33 hours after the last evening's BIDdose, the difference in the total draw time, i.e., 10.33 hours, may varyby as much as about +/−60 minutes and preferably no more than about+/−20 minutes between one another. It should also be understood thatwhile, serum total testosterone level values for PK samples is 755 ng/dLis the preferred level to use to determine if titration to TID isnecessary, the serum total testosterone level values for PK samples mayvary as much as +/−50 and preferably no more than +/−25.

As an alternative, it should be understood that, while the titrationmethod is described above with starting the titration method based uponthe last evening's BID dose, the titration method could also be used bystarting the titration method based upon the first morning dose. Forexample, under this alternative embodiment, the first blood draw wouldbe taken at about 9 hours and the second blood draw would be taken atabout 10.33 hours after the morning dose, so long as the second blooddraw is taken at about 20 minutes after the last BID dose of the day.

Thus, a titration method in accordance with the present invention foroptimizing a treatment regimen for treating a male diagnosed withhypogonadism with an intranasal testosterone gel comprises:

-   -   (a) administering intranasally to the male the intranasal        testosterone gel twice daily for a selected number of days;    -   (b) extracting a first blood sample from the male at a selected        time before a selected dose (first or second dose) of the twice        daily treatment regimen on the first day after the selected        number of days;    -   (c) extracting a second blood sample from the male at a selected        time after administration of the selected dose of the twice        daily treatment regimen on the first day after the selected        number of days;    -   (d) measuring the testosterone serum level in the first blood        sample to generate a first testosterone ng/dl measurement;    -   (e) measuring the testosterone serum level in the second blood        sample to generate a second testosterone ng/dl measurement;    -   (f) adding the first testosterone measurement and the second        testosterone measurement together to generate a serum        testosterone ng/dl concentration sum for predicting a        testosterone C_(avg) for the male; and    -   (g) comparing the serum testosterone concentration sum to a        target serum testosterone level to determine an optimized        intranasal treatment regimen for treating the male with the        intranasal testosterone gel for maintaining in the male a        testosterone 24 hour serum average at a level of at least about        300 ng/dl during the optimized treatment regimen; and

wherein, if the serum testosterone concentration sum is (i) less thanthe target serum testosterone level, titrating the twice dailyintranasal treatment regimen for the male to a treatment regimen that isthree times a day (TID) to treat the male for hypogonadism, or (ii) isequal to or greater than the target serum testosterone level, continuingwith the twice daily intranasal treatment regimen for the male to treatthe male for hypogonadism.

The present invention is also directed to packaged pharmaceuticalscomprising the novel and improved testosterone gel formulations fornasal administration of the invention. For example, the presentinvention contemplates pre-filled, single or multi-dose applicatorsystems for pernasal administration to strategically and uniquelydeposit the nasal testosterone gels at the preferred locations withinthe nasal cavity for practicing the novel methods and teachings of thepresent invention. Generally, speaking the applicator systems of thepresent invention are, e.g., airless fluid, dip-tube fluid dispensingsystems, pumps, pre-filled, unit-dose syringes or any other systemsuitable for practicing the methods of the present invention. Theapplicator systems or pumps include, for example, a chamber, pre-filledwith a single dose or multiple doses of an intranasal testosterone gelof the present invention, that is closed by an actuator nozzle or cap.The actuator nozzle may comprise an outlet channel and tip, wherein theactuator nozzle is shaped to conform to the interior surface of a user'snostril for (a) consistent delivery of uniform dose amounts of anintranasal testosterone gel of the present invention during pernasalapplication within the nasal cavity, and (b) deposition at theinstructed location within each nostril of a patient as contemplated bythe novel methods and teachings of the present invention. Preferably,when inserted into a nasal cavity, the pump design is configured to helpensure that the nasal tip is properly positioned within the nasal cavityso that, when the gel is dispensed, the gel is dispensed within theappropriate location within the nasal cavity. See Steps 3 and 8 in FIG.10A. Additionally, the nozzles of to pumps are preferably designed todispense the gels from the side in a swirl direction, i.e., the tips ofthe nozzles are designed to dispense in a side distribution direction,as opposed to a direct distribution direction, onto the nasal mucosa, asshown in steps 4 and 9 of FIG. 10A. It is believed that the swirl actionallows for better gel adhesion and side distribution from the nozzle tipavoids the dispensed gel from splashing back onto the tip. Finally, itis preferred to design the nozzle and tip to allow for any residual gelon the nozzle/tip to be wiped off as the tip is removed from the nasalcavity. See, e.g., FIGS. 10A and 10B. Examples of pre-filled, multi-doseapplicator systems include, e.g., (a) the COMOD system available fromUrsatec, Verpackung-GmbH, Schillerstr. 4, 66606 St. Wendel, Germany, (b)the Albion or Digital airless applicator systems available fromAirlessystems, RD 149 27380 Charleval, France or 250 North Route 303Congers, N.Y. 10950, (c) the nasal applicators from Neopac, The Tube,Hoffmann Neopac AG, Burgdorfstrasse 22, Postfach, 3672 Oberdiessbach,Switzerland, or (d) the syringes described in the Examples herein below.

A nasal multi-dose dispenser device according to embodiments of thepresent invention, such as the Albion or Digital airless applicatorsystems available from Airlessystems, is comprised of a fluid containerand a distributor pump for delivery of multiple doses of a gel or othertopical formulation. In one embodiment of the present invention, thenasal multi-dose dispenser device is adapted for an airless fluiddispensing system. In another embodiment of the present invention, thenasal multi-dose dispenser device is adapted for a dip tube fluiddispensing system.

An example of an airless system that is contemplated by the presentinvention is one that will deliver a liquid, including gel, without theneed for a pressured gas or air pump to be in contact with the liquid(or gel). In general, an airless system of the present inventioncomprises a flexible pouch containing the liquid, a solid cylindricalcontainer a moving piston, an aspirating pump, a dosing valve and adelivery nozzle, as depicted, for example, in FIGS. 1-4 . See also FIGS.7A, 7B, 8A, 8B, 9A, 9B, 10A, 10B and 11 .

In accordance with the present invention, the multi-dose dispenser 100of FIG. 1 is provided with a fluid container 120, a distributor pump 140and a cap 102.

The fluid container 120 comprises a container body 122, a base 124 and aneck 126. The distributor pump 140 is fastened to the neck by a sleeve128. The top end of the container body 122 is closed by the distributorpump 140. The sleeve 128 tightly pinches a neck gasket 150 against thetop end of the container body 122. The container body 122 forms a vacuumand houses the fluid to be dispensed.

The distributor pump 140 is closed by its actuator nozzle 130, whichretains the stem 144 at the stem head. The actuator nozzle 130 comprisesan outlet channel 132 and tip 134.

The actuator nozzle 130 is shaped to conform with the interior surfaceof a user's nostril. The actuator nozzle 130 is moveable between adownward open position and upward closed position. The user removes thecap 102 and inserts the actuator nozzle 130 in the user's nostril. Whenthe user pushes the actuator nozzle 130 downwards to the open position,fluid in the dosing chamber 180 is withdrawn by the distributor pump 140and exits at the tip 134 via the outlet channel 132 of the actuatornozzle 130.

FIG. 2 shows a cross-sectional view of the distributor pump 140.

The distributor pump has a body 142 provided with a bottom intake havingan inlet valve 160 with a ball 162 as its valve member. The ball 162 isheld in place by a cage 164 and by a return spring 170.

At its bottom end, the stem 144 carries a spring cap 172. A piston 174is located above the spring cap 172. The stem 144 passes through anaxial orifice of the piston base 176.

The side walls of the piston 174 seals against the distributor pump body142 via lips. The sleeve 128 tightly pinches a stem gasket 152 againstthe stem collar 146, distributor pump body 142 and top of the piston174.

A precompression spring 178 placed between the piston base 176 and thestem collar 146. The precompression spring 178 biases the actuatornozzle 130 via the stem 144 to the closed position.

The return spring 170, which returns the piston 174 back upwards, iscompressed between two opposed seats on the cage 164 and the spring cap172.

The distributor pump 140 has a dosing chamber 180 formed between thecage 164 and piston 174. When the user pushes the actuator nozzledownwards to the open position, fluid in the dosing chamber is withdrawnby the distributor pump 140 and dispensed from the tip of the actuatornozzle 130.

When the user releases the actuator nozzle 130 upwards to the closedposition, a fluid in the container body 122 is withdrawn into the dosingchamber 180 by the distributor pump 140. Thus, a dose of fluid is readyfor the next actuation of the actuator nozzle by the user.

In another embodiment of the present invention, the dispenser 200 ofFIG. 3 is provided with a fluid container 220, a distributor pump 240and a cap 202.

The fluid container 220 comprises a container body 222, a base 224 and aneck 226. The distributor pump 240 is fastened to the neck by a sleeve228. The top end of the container body 222 is closed by the distributorpump 240. The sleeve 228 tightly pinches a neck gasket 250 against thetop end of the container body 222. The container body 222 houses thefluid to be dispensed.

The distributor pump 240 is closed by its actuator nozzle 230, whichretains the stem 244 at the stem head. The actuator nozzle 230 comprisesan outlet channel 232 and tip 234. The actuator nozzle 230 is shaped toconform with the interior surface of a user's nostril. The actuatornozzle 230 is moveable between a downward open position and upwardclosed position. The user removes the cap 202 and inserts the actuatornozzle 230 in the user's nostril. When the user pushes the actuatornozzle 230 downwards to the open position, fluid in the dosing chamber280 is withdrawn by the distributor pump 240 and exits at the tip 234via the outlet channel 232 of the actuator nozzle 230.

FIG. 4 shows a cross-sectional view of the distributor pump 240.

The distributor pump has a body 242 provided with a bottom intake havingan inlet valve 260 with a ball 262 as its valve member. The ball 262 isheld in place by a cage 264 and by a return spring 270. Optionally, adip tube 290 can extend downward from the inlet valve 260 and isimmersed in the liquid contained in the container body.

At its bottom end, the stem 244 carries a spring cap 272. A piston 274is located above the spring cap 272. The stem 244 passes through anaxial orifice of the piston base 276.

The side walls of the piston 274 seals against the distributor pump body242 via lips. The sleeve 228 tightly pinches a stem gasket 252 againstthe stem collar 246, distributor pump body 242 and top of the piston274.

A precompression spring 278 placed between the piston base 276 and thestem collar 246. The precompression spring 278 biases the actuatornozzle 230 via the stem 244 to the closed position.

The return spring 270, which returns the piston 274 back upwards, iscompressed between two opposed seats on the cage 264 and the spring cap272. The distributor pump 240 has a dosing chamber 280 formed betweenthe cage 264 and piston 274. When the user pushes the actuator nozzledownwards to the open position, air enters the dosing chamber 280, whichforces the fluid in the dosing chamber to be withdrawn by thedistributor pump 240 and dispensed from the tip of the actuator nozzle230.

When the user releases the actuator nozzle 230 upwards to the closedposition, the air contained in the dosing chamber 280 forces the fluidin the container body 222 to be withdrawn into the dosing chamber 280.Thus, a dose of fluid is ready for the next actuation of the actuatornozzle by the user.

The amount of fluid withdrawn by the distributor pump into the dosingchamber may be a fixed volume. The distributor pumps may be of a varietyof sizes to accommodate a range of delivery volumes. For example, adistributor pump may have a delivery volume of 140 μl.

The dispensers of the present invention may dispense topical intranasalgel or other topical intranasal formulations, preferably pernasally,which contain alternative or additional active ingredients, such asneurosteroids or sexual hormones (e.g., androgens and progestins, liketestosterone, estradiol, estrogen, oestrone, progesterone, etc.),neurotransmitters, (e.g., acetylcholine, epinephrine, norepinephrine,dopamine, serotonin, melatonin, histamine, glutamate, gamma aminobutyricacid, aspartate, glycine, adenosine, ATP, GTP, oxytocin, vasopressin,endorphin, nitric oxide, pregnenolone, etc.), prostaglandin,benzodiazepines like diazepam, midazolam, lorazepam, etc., and PDEFinhibitors like sildenafil, tadalafil, vardenafil, etc., in the form ofa liquid, cream, ointment, salve or gel. The dispensers may be suitablefor cosmetic, dermatological or pharmaceutical applications. Examples oftopical intranasal formulations for topical pernasal application, whichcan be dispensed in accordance with the present invention include thepernasal testosterone gels of the present invention or other intranasaltopical gels wherein the testosterone is replaced or combined with aanother active ingredient in effective amounts, such as those activeingredients discussed herein above. In addition, other testosteroneformulations suitable and contemplated for dispensing from thedispensers and/or in accordance with the methods of the presentinvention include the formulations disclosed in, for example, U.S. Pat.Nos. 5,578,588, 5,756,071 and 5,756,071 and U.S. Patent Publication Nos.2005/0100564, 2007/0149454 and 2009/0227550, all of which areincorporated herein by reference in their entireties.

It should be understood by those versed in this art that the amount oftestosterone in a lower dosage strength intranasal testosterone gel ofthe present invention that will be therapeutically effective in aspecific situation will depend upon such things as the dosing regimen,the application site, the particular gel formulation, dose longevity andthe condition being treated. As such, it is generally not practical toidentify specific administration amounts herein; however, it is believedthat those skilled in the art will be able to determine appropriatetherapeutically effective amounts based on the guidance provided herein,information available in the art pertaining to testosterone replacementtherapy, and routine testing.

It should be further understood that the above summary of the presentinvention is not intended to describe each disclosed embodiment or everyimplementation of the present invention. The description furtherexemplifies illustrative embodiments. In several places throughout thespecification, guidance is provided through examples, which examples canbe used in various combinations. In each instance, the examples serveonly as representative groups and should not be interpreted as exclusiveexamples.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other objects, advantages and features of the presentinvention, and the manner in which the same are accomplished, willbecome more readily apparent upon consideration of the followingdetailed description of the invention taken in conjunction with theaccompanying figures and examples, which illustrate embodiments,wherein:

FIG. 1 is a side view of a first embodiment of the invention;

FIG. 2 is a cross-sectional side view of the distributor pump of thefirst embodiment of the invention;

FIG. 3 is a side view of a second embodiment of the invention;

FIG. 4 is a cross-sectional side view of the distributor pump of thesecond embodiment of the invention;

FIG. 5 is a side view of a second embodiment of the invention concerningan airless bottle assembly of the invention;

FIG. 6 is a side view of a second embodiment of the invention concerningdigital actuator and rounded cap;

FIG. 7A depicts the right nostril of subject #1 after a single dosesyringe administration;

FIG. 7B depicts the left nostril of subject #1 after a multiple dosedispenser administration;

FIG. 8A depicts the right nostril of subject #2 after a single dosesyringe administration;

FIG. 8B depicts the left nostril of subject #2 after a multiple dosedispenser administration;

FIG. 9A depicts the right nostril of subject #3 after a single dosesyringe administration;

FIG. 9B depicts the left nostril of subject #3 after a multiple dosedispenser administration;

FIGS. 10A and 10B illustrate use of a multiple dose dispenser inaccordance with the present invention;

FIG. 11 illustrates a multiple dose dispenser in accordance with thepresent invention;

FIG. 12 depicts a Franz Cell apparatus position layouts for comparingtesting in accordance with Example 5;

FIG. 13 is a graph showing the change in testosterone levels in serumover time for a 4.5% testosterone bio-adhesive gel administered in eachnostril of a hypogonadal male twice daily in accordance with the presentinvention as compared to normal testosterone pharmacokinetics in younghealthy adult males, as reported in Diver M J. et al: Diurnal rhythms oftotal, free and bioavailable testosterone and of SHBG in middle-aged mencompared with those in young men. Clinical Endocrinology, 58: 710-717(2003);

FIG. 14 depicts a comparison between TBS 1 A 8% (Part I);

FIG. 15 depicts a comparison between TBS 1 A 8% (Part I);

FIG. 16 depicts a comparison between 6 hours and 24 hours run (RD11101and RD11102)

FIG. 17 depicts a comparison between TBS 1 A 4% (Part I);

FIG. 18 depicts a comparison between TBS 1 A 4% (Part II);

FIG. 19 depicts a comparison between TBS 1 A 4% (Part III);

FIG. 20 depicts a comparison slower diffusion;

FIG. 21 depicts a comparison between 6 hours and 24 hours run (RD11063and RD11085);

FIG. 22 depicts a comparison between 400 mg and 1 gram of gel (RD11063);

FIG. 23 depicts individual amount of testosterone released from thecompositions in accordance with Example 12;

FIG. 24 depicts individual testosterone concentration versus time(linear y-axis), that are grouped by subject in accordance with Example13. Number. Black: baseline; blue: syringe; salmon: multiple dosedispenser. T=0 is at 21:00 clock-time (±30 minutes), t=12 is at 9:00(±30 minutes) clock-time;

FIG. 25 depicts individual (blue) and median (black) testosteroneconcentration versus time (linear y-axis), that are grouped bytreatment;

FIG. 26 depicts the probability density of the log ratio of testosteronelevels that are reached with the multiple dose dispenser over levelsthat are reached with the syringe;

FIG. 27 depicts solubility of testosterone in different vehicles at 32°C. and at 50° C.;

FIG. 28 depicts Ternary solvent mixture optimization: Contour plot showsthat, in order to achieve more than 6% testosterone solubility, higherlevels of DMI and Transcutol are required;

FIG. 29 depicts a flow diagram for manufacturing TBS-1.

FIG. 30A and FIG. 30B depict a flow diagram of a manufacturing processof an intranasal testosterone gel of the present invention;

FIG. 31 depicts a mean concentration-time curves of testosterone (solidsquares) and DHT (open squares) after single-dose administration of 3different TBS-1 strengths (7.6 mg=squares; 15.2 mg=circles; 22.8 mgtriangles). The lower limit of normal range for testosterone isindicated with the dashed line (based on morning serum samples);

FIG. 32 depicts testosterone diffusion rate of intranasal testosteronegel formulations of Example 13 using Franz cells method;

FIG. 33 depicts the pharmacokinetic profiles of 15 male subjects usingthe formulas of Example 13;

FIG. 34 is an operational diagram for manufacturing the testosterone gelformulations in accordance with the invention;

FIG. 35 depicts the mean testosterone serum concentration time profile;

FIG. 36 depicts the mean dihydrotestosterone serum concentration timeprofile;

FIG. 37 depicts the mean estradiol serum concentration time profile;

FIG. 38 depicts the peak response as a function of dosage;

FIG. 39 depicts the active release amount over time;

FIG. 40 depicts titration model results with testosterone Sample A taken1 hour before morning dose and testosterone Sample B taken 20 minutesafter morning dose;

FIG. 41 depicts titration model results with testosterone Sample A taken1 hour before morning dose and testosterone Sample B taken 40 minutesafter morning dose;

FIG. 42 depicts titration model results with testosterone Sample A taken1 hour before morning dose and testosterone Sample B taken 60 minutesafter morning dose;

FIG. 43 depicts titration model results with testosterone Sample A taken1 hour before morning dose and testosterone Sample B taken 90 minutesafter morning dose;

FIG. 44 depicts a linear-scale mean serum concentration time plot fortestosterone;

FIG. 45 depicts a linear-scale mean serum concentration time plot fortestosterone;

FIG. 46 depicts a scale indicating testosterone and concentration vs.

FIG. 47 depicts the In Vitro Release Rate (IVRT) testing results and newdata.

DETAILED DESCRIPTION

By way of illustrating and providing a more complete appreciation of thepresent invention and many of the attendant advantages thereof, thefollowing detailed description and examples are given concerning thenovel lower dosage strength intranasal testosterone gels, applicationdevices and methods of the present invention.

As used in the description of the invention and the appended claims, thesingular forms “a”, “an” and “the” are used interchangeably and intendedto include the plural forms as well and fall within each meaning, unlessthe context clearly indicates otherwise. Also, as used herein, “and/or”refers to and encompasses any and all possible combinations of one ormore of the listed items, as well as the lack of combinations wheninterpreted in the alternative (“or”).

As used herein, “at least one” is intended to mean “one or more” of thelisted elements.

Singular word forms are intended to include plural word forms and arelikewise used herein interchangeably where appropriate and fall withineach meaning, unless expressly stated otherwise.

Except where noted otherwise, capitalized and non-capitalized forms ofall terms fall within each meaning.

Unless otherwise indicated, it is to be understood that all numbersexpressing quantities, ratios, and numerical properties of ingredients,reaction conditions, and so forth used in the specification and claimsare contemplated to be able to be modified in all instances by the term“about”.

All parts, percentages, ratios, etc. herein are by weight unlessindicated otherwise.

As used herein, “bioequivalence” or “bioequivalent”, refers to nasallyadministered testosterone gel formulations or drug products which arepharmaceutically equivalent and their bioavailabilities (rate and extentof absorption) after administration in the same molar dosage or amountare similar to such a degree that their therapeutic effects, as tosafety and efficacy, are essentially the same. In other words,bioequivalence or bioequivalent means the absence of a significantdifference in the rate and extent to which testosterone becomesavailable from such formulations at the site of testosterone action whenadministered at the same molar dose under similar conditions, e.g., therate at which testosterone can leave such a formulation and the rate atwhich testosterone can be absorbed and/or become available at the siteof action to affect TRT, including hypogonadism. In other words, thereis a high degree of similarity in the bioavailabilities of twotestosterone gel formulation pharmaceutical products for nasaladministration (of the same galenic form) from the same molar dose, thatare unlikely to produce clinically relevant differences in therapeuticeffects, or adverse reactions, or both. The terms “bioequivalence”, aswell as “pharmaceutical equivalence” and “therapeutic equivalence” arealso used herein as defined and/or used by (a) the FDA, (b) the Code ofFederal Regulations (“C.F.R.”), Title 21, (c) Health Canada, (d)European Medicines Agency (EMEA), and/or (e) the Japanese Ministry ofHealth and Welfare. Thus, it should be understood that the presentinvention contemplates testosterone gel formulations for nasaladministration or drug products that may be bioequivalent to othertestosterone gel formulations for nasal administration or drug productsof the present invention. By way of example, a first testosterone gelformulation for nasal administration or drug product is bioequivalent toa second testosterone gel formulation for nasal administration or drugproduct, in accordance with the present invention, when the measurementof at least one pharmacokinetic parameter(s), such as a Cmax, Tmax, AUC,etc., of the first testosterone gel formulation for nasal administrationor drug product varies by no more than about ±25%, when compared to themeasurement of the same pharmacokinetic parameter for the secondtestosterone gel formulation for nasal administration or drug product ofthe present invention.

As used herein, “bioavailability” or “bioavailable”, means generally therate and extent of absorption of testosterone into the systemiccirculation and, more specifically, the rate or measurements intended toreflect the rate and extent to which testosterone becomes available atthe site of action or is absorbed from a drug product and becomesavailable at the site of action. In other words, and by way of example,the extent and rate of testosterone absorption from a lower dosagestrength gel formulation for nasal administration of the presentinvention as reflected by a time-concentration curve of testosterone insystemic circulation.

As used herein, the terms “pharmaceutical equivalence” or“pharmaceutically equivalent”, refer to testosterone gel formulationsfor nasal administration or drug products of the present invention thatcontain the same amount of testosterone, in the same dosage forms, butnot necessarily containing the same inactive ingredients, for the sameroute of administration and meeting the same or comparable compendial orother applicable standards of identity, strength, quality, and purity,including potency and, where applicable, content uniformity and/orstability. Thus, it should be understood that the present inventioncontemplates testosterone gel formulations for nasal administration ordrug products that may be pharmaceutically equivalent to othertestosterone gel formulations for nasal administration or drug productsused in accordance with the present invention.

As used herein, “therapeutic equivalence” or “therapeuticallyequivalent”, means those testosterone gel formulations for nasaladministration or drug products which (a) will produce the same clinicaleffect and safety profile when utilizing testosterone drug product forTRT and to treat testosterone deficiency, including hypogonadism, inmale subjects in accordance with the present invention and (b) arepharmaceutical equivalents, e.g., they contain testosterone in the samedosage form, they have the same route of administration; and they havethe same testosterone strength. In other words, therapeutic equivalencemeans that a chemical equivalent of a lower dosage strength testosteroneformulation of the present invention (i.e., containing the same amountof testosterone in the same dosage form when administered to the sameindividuals in the same dosage regimen) will provide essentially thesame efficacy and toxicity.

As used herein a “testosterone gel formulation for nasal administration”means a formulation comprising testosterone in combination with asolvent, a wetting agent, and a viscosity increasing agent.

As used herein, “plasma testosterone level” means the level oftestosterone in the plasma of a subject. The plasma testosterone levelis determined by methods known in the art.

“Diagnosis” or “prognosis,” as used herein, refers to the use ofinformation (e.g., biological or chemical information from biologicalsamples, signs and symptoms, physical exam findings, psychological examfindings, etc.) to anticipate the most likely outcomes, timeframes,and/or responses to a particular treatment for a given disease,disorder, or condition, based on comparisons with a plurality ofindividuals sharing symptoms, signs, family histories, or other datarelevant to consideration of a patient's health status, or theconfirmation of a subject's affliction, e.g., testosterone deficiency,including hypogonadism.

A “subject” according to some embodiments is an individual whose signsand symptoms, physical exams findings and/or psychological exam findingsare to be determined and recorded in conjunction with the individual'scondition (i.e., disease or disorder status) and/or response to acandidate drug or treatment.

“Subject,” as used herein, is preferably, but not necessarily limitedto, a human subject. The subject may be male or female, and ispreferably female, and may be of any race or ethnicity, including, butnot limited to, Caucasian, African-American, African, Asian, Hispanic,Indian, etc. Subject as used herein may also include an animal,particularly a mammal such as a canine, feline, bovine, caprine, equine,ovine, porcine, rodent (e.g., a rat and mouse), a lagomorph, a primate(including non-human primate), etc., that may be treated in accordancewith the methods of the present invention or screened for veterinarymedicine or pharmaceutical drug development purposes. A subjectaccording to some embodiments of the present invention include apatient, human or otherwise, in need of therapeutic treatment oftestosterone deficiency, including hypogonadism.

“Treatment,” as used herein, includes any drug, drug product, method,procedure, lifestyle change, or other adjustment introduced in attemptto effect a change in a particular aspect of a subject's health (i.e.,directed to a particular disease, disorder, or condition).

“Drug” or “drug substance,” as used herein, refers to an activeingredient, such as a chemical entity or biological entity, orcombinations of chemical entities and/or biological entities, suitableto be administered to a male subject to treat testosterone deficiency,including hypogonadism. In accordance with the present invention, thedrug or drug substance is testosterone or a pharmaceutically acceptablesalt or ester thereof.

The term “drug product,” as used herein, is synonymous with the terms“medicine,” “medicament,” “therapeutic intervention,” or “pharmaceuticalproduct.” Most preferably, a drug product is approved by a governmentagency for use in accordance with the methods of the present invention.A drug product, in accordance with the present invention, is anintranasal gel formulated with a drug substance, i.e., testosterone.

“Disease,” “disorder,” and “condition” are commonly recognized in theart and designate the presence of signs and/or symptoms in an individualor patient that are generally recognized as abnormal and/or undesirable.Diseases or conditions may be diagnosed and categorized based onpathological changes. The disease or condition may be selected from thetypes of diseases listed in standard texts, such as Harrison'sPrinciples of Internal Medicine, 1997, or Robbins Pathologic Basis ofDisease, 1998.

As used herein, “diagnosing” or “identifying a patient or subject havingtestosterone deficiency, such as hypogonadism, refers to a process ofdetermining if an individual is afflicted with testosterone deficiency,such as hypogonadism.

As used herein, “control subject” means a subject that has not beendiagnosed with testosterone deficiency or hypogonadism and/or does notexhibit any detectable symptoms associated with these diseases. A“control subject” also means a subject that is not at risk of developingtestosterone deficiency or hypogonadism, as defined herein.

The testosterone gel formulations of the invention are viscous andthixotropic, oil-based formulations containing a solution oftestosterone intended for intranasal application. The non-irritatingformulation is designed to adhere to the inner nose. In addition, itacts as a controlling matrix, thus allowing sustained drug deliverythrough the nasal mucosa.

Other pharmacologically inactive ingredients in the testosteroneintranasal gel are castor oil USP, oleoyl macrogolglycerides EP andcolloidal silicon dioxide NF. None of these excipients are of human oranimal origin. All excipients are well-known and listed in the “InactiveIngredient” list for Approved Drug Products issued by the FDA.

The steroid hormone testosterone is the active ingredient in thetestosterone gel formulations of the invention. The manufacture of thedrug substance presents no potential risk for humans; the synthesisroute is well-characterized,

TABLE 1 Nomenclature Testosterone INN name Testosterone Compendial nameTestosterone Chemical name 17β-Hydroxyandrost-4-en-3-one Othernon-proprietary Androst-4-en-3-one, 17-hydroxy-, names(17β)-Trans-testosterone Δ4-androsten-17β-ol-3-one CAS registry number58-22-0 Proquina code 8139

Molecular FormulaC₁₉H₂₈O₂Relative Molecular Mass288.4

The physical chemical properties of testosterone are listed in Table 2.

TABLE 2 General Properties of Testosterone Appearance White or slightlycreamy white crystals or crystalline powder. It is odourless, and stablein air. Solubility Practically insoluble in water (0.024 g/L), freelysoluble in dehydrated alcohol, chloroform and in methylene chloride,soluble in dioxane and in vegetable oils; slightly soluble in ether.Melting range 153° C. to 157° C. Specific rotation +101° to +105°(dioxane) Loss on drying Not more than 1.0% UV max 238 nm StorageProtected from light

Testosterone, for testosterone gel formulations of the invention,appears as white or slightly creamy white crystals or crystallinepowder. It is freely soluble in methanol and ethanol, soluble in acetoneand isopropanol and insoluble in n-heptane. It can also be considered asinsoluble in water (S_(20° C.)=2.41×10⁻² g/L±0.04×10⁻² g/L); itsn-Octanol/Water partition coefficient (log P_(OW) determined by HPLC) is2.84. The solubility of testosterone in oils was determined to be 0.8%in isopropylmyristate, 0.5% in peanut oil, 0.6% in soybean oil, 0.5% incorn oil, 0.7% in cottonseed oil and up to 4% in castor oil.

Because testosterone is fully dissolved within the formulations of thepresent invention, physical characteristics of the drug substance do notinfluence the performance of the drug product, testosterone gelformulations of the invention. The manufacturability of testosterone gelformulations of the invention, however is influenced by the particlesize of testosterone. When using a particle size of 50%≤25 microns,90%≤50 microns the solubility of the drug substance in the matrix isespecially favorable.

In accordance with the present invention, the testosterone drug can bein, for instance, crystalline, amorphous, micronized, non-micronized,powder, small particle or large particle form when formulating tointranasal testosterone gels of the present invention. An Exemplaryrange of testosterone particle sizes include from about 0.5 microns toabout 200 microns. Preferably, the testosterone particle size is in arange of from about 5 microns to about 100 microns, and the testosteroneis in crystalline or amorphous and non-micronized or micronized form.Preferably, the testosterone is in crystalline or amorphous micronizedform.

The molecular structure of testosterone contains no functional groupsthat can be protonated or deprotonated in the physiological pH-range.Therefore testosterone is to be considered as a neutral molecule with nopKa value in the range 1-14. Because it is neutral, testosterone iscompatible with excipients.

The testosterone gel formulations of the invention are viscous andthixotropic, oil-based formulations containing a solution oftestosterone intended for intranasal application. The non-irritatingformulation is designed to adhere to the inner nose. In addition, itacts as a controlling matrix, thus allowing sustained drug deliverythrough the nasal mucosa.

Other pharmacologically inactive ingredients in the testosteroneintranasal gel are castor oil USP, oleoyl macrogolglycerides EP andcolloidal silicon dioxide NF. None of these excipients are of human oranimal origin. All excipients are well-known and listed in the “InactiveIngredient” list for Approved Drug Products issued by the FDA.

According to the “Handbook of Pharmaceutical Additives” oleoylpolyoxylglycerides are used as hydrophilic oil for topicals, injectablesand nasals. In FDA-approved medicinal products it is used asco-emulsifier in topical emulsions/lotions/creams and in vaginalemulsions/creams. In France this excipient is approved for nasalpreparations such as “Rhino-Sulforgan” (Laboratoire Jolly-Jatel, France;containing 10% oleoyl polyoxylglycerides) and “Huile Gomenolee 2%(“Laboratoire Goménol, France; containing 10% oleoylpolyoxylglycerides). Hence, like for castor oil it can be deduced thatoleoyl polyoxylglycerides is suitable for an application route wheresafety and tolerability are of highest importance (e.g. injectables andnasal or vaginal preparations).

Oleoyl macrogolglycerides are also referred to as Labrafil M 1944 CS,apricot kernel oil PEG-6 esters, Peglicol-5-oleate, mixture ofglycerides and polyethylene esters. The castor oil, which is used as asolvent for testosterone gel formulations of the invention, is a fixedoil. Such oils have the advantage of being non-volatile or spreading (incontrast to essential oils or liquid paraffin), but have thedisadvantage of being hydrophobic. The nasal mucosa contains 95-97%water. Without the oleoyl macrogol-glycerides, the castor oil containingthe active ingredient would form a non-interactive layer on the mucousmembrane. In order to achieve adequate contact between the castor oillayer and the mucous membrane, the hydrophilic oleoylmacrogol-glycerides oil is added to the formulation to form an emulsionbetween the castor oil and the mucosa fluid.

Oleoyl macrogolglycerides are used in semi-solids at concentrationsranging from about 3 to 20%, depending on the application. The amount ofoleoyl macrogol-glycerides in testosterone gel formulations of theinvention is high enough to allow for a better contact of the carrieroil with the mucous membrane and low enough to have minimal impact onthe amount of testosterone that can be incorporated into the carrieroil. A favourable concentration of oleoyl microgol-glycerides intestosterone gel formulations of the invention is found to be 4% of theformulation.

According to the “Handbook of Pharmaceutical Additives” colloidalsilicon dioxide is used as an oil adsorbent, thermal stabiliser andgellant. In FDA-approved medicinal products it is used in dental gels,sublingual tablets, endocervical gel, suppositories, vaginalemulsions/creams/tablets/tampons and capsules for inhalation.Furthermore, it is used as an excipient in “Testoderm with adhesives”(Alza Corporation, approved in 1996) a testosterone transdermal patch.Hence, it can be deduced that colloidal silicon dioxide is suitable foran application route where safety and tolerability are of highestimportance (e.g. inhalations, endocervical, vaginal or rectalpreparations).

For clinical trial supplies, testosterone intranasal gel is supplied inunit-dose syringes consisting of a syringe body made from polypropylene,a plunger moulded from polyethylene and a syringe cap made from highdensity polyethylene. The syringes are wrapped in aluminum foil assecondary packaging. The pre-filled unit-dose syringes used inaccordance with the study in the Examples are filled as follows: (a) 4%testosterone intranasal bio-adhesive gel—148 microliters and 5.92 mgs oftestosterone; (b) 4.5% testosterone intranasal bio-adhesive gel—148microliters and 6.66 mgs of testosterone; and (c) 4.5% testosteroneintranasal bio-adhesive gel—148 microliters and 7.785 mgs oftestosterone.

The oil in testosterone gel formulations of the invention is thickenedwith colloidal silicon dioxide, which acts as a gel-forming agent. Thiscompound is used commonly for stiffening oleogels.

The intended dosage form for testosterone gel formulations of theinvention is a semi-solid, not a liquid. The formulation is thickenedwith colloidal silicon dioxide. It is believed that colloidal silicondioxide contributes to the thixotropic properties of the gel,simplifying drug delivery to the nostril.

Colloidal silicon dioxide is generally an inert material which is welltolerated as an excipient in mucosal applications such as suppositories.Colloidal silicon dioxide is typically used in these preparations atconcentrations ranging from about 0.5 to 10%. The concentration ofcolloidal silicon dioxide in testosterone gel formulations of theinvention is high enough to achieve gel formation but at a level thathas minimal impact on testosterone incorporation into the carrier oil.

Preferably, the intranasal testosterone gels of the present inventionhave in general, a viscosity in the range of between about 3,000 cps andabout 27,000 cps. It should nevertheless be understood by those versedin this art that, while the above-mentioned viscosity range is believedto be a preferred viscosity range, any suitable viscosities or viscosityranges that do not defeat the objectives of the present invention arecontemplated.

A detailed description of batches of a testosterone gel formulation ofthe invention is shown in Table 3.

TABLE 3 Composition of a testosterone gel formulation of the inventionAmount Amount (% w/w) (% w/w) Component 4.0% 0.45% Testosterone 4.0% 4.5% Castor oil  88% 87.5% Oledyl macrogol- 4.0%  4.0% glyceridesColloidal silicon dioxide 4.0%  4.0%

The testosterone gel formulations of the invention are stored at roomtemperature (20-25° C. or 68 to 77° F.). Temperature excursions from 15to 30° C. or 59 to 86° F. are permissible for the testosterone gelformulations of the inventions. The stability data supports a 12-monthshelf life. Unit dose syringes are chosen for the primary packaging ofthe clinical materials for the clinical trial described below to allowfor ease of dosing, ability to generate multiple doses by varying thefill volume and consistency of dose delivered. The syringe consists of asyringe body, a plunger and a syringe cap. The syringes body is mouldedfrom polypropylene, the plunger is moulded from polyethylene and the capis HDPE. These syringes are designed and manufactured to deliver sterileand non-sterile solutions, liquids and gels at low volumes. Foradditional protection from the environment (i.e., exposure to dirt,light, humidity and oxygen), the syringes are packed in a foil-laminateoverwrap pouch.

The syringes and caps are designed for use in a clinical setting andmeet the requirements of the EU Medical Devices Directive 93/42/EEC ofJun. 14, 1993 and as amended. As this container closure is only intendedfor use in this portion of the clinical program, no additional studieswill be performed on the syringe and syringe components.

For a further element of protection, two syringes are contained insecondary packaging consisting of an aluminium foil pouch. Two syringesare packaged in the aluminium foil pouch and each pouch is sealed.

The pouch consists of a flexible, 3-layered-foil-laminate of a)polyester 12 micron, b) aluminum 12 micron and c) a polyethylene 75micron. It is manufactured by Floeter Flexibles GmbH, and supplied underthe name “CLIMAPAC II 12-12-75”.

The invention provides for intranasal bio-adhesive gel formulations oftestosterone to be administered intranasally, wherein the dosage of theformulation is from about 4.0% or 4.5% testosterone by weight of saidgel.

The methods and treatments of the present invention are suitable for TRTin men and are especially suitable to treat testosterone deficient malesubjects, such as those who are diagnosed with hypogonadism.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, suitable methods andmaterials are described below. All publications, patent applications,patents, and other references mentioned herein are incorporated byreference in their entirety. In case of conflict, the presentspecification, including definitions, will control. In addition, thematerials, methods, and examples are illustrative only and not intendedto be limiting.

EXAMPLES

Having now generally described the invention, the same will be morereadily understood through reference to the following Examples which areprovided by way of illustration, and are not intended to be limiting ofthe present invention, unless specified.

The following examples are put forth for illustrative purposes only andare not intended to limit the scope of what the inventors regard astheir invention.

Example 1 Description and Composition of Testosterone Gel Formulationsof the Invention

The compositions of three different concentrations of the drug productto be administered in this clinical trial are provided in the tablesbelow.

Description of Dosage Form

The testosterone gel formulations of the invention are viscous andthixotropic, oil-based formulations containing solubilized testosteroneintended for intranasal application. The drug product is formulated withthe compendial inactive ingredients: castor oil, oleoylpolyoxylglycerides and colloidal silicon dioxide.

Two different doses of the testosterone gel formulations of theinvention are intranasally administered: 0.4% w/w and 0.45% w/w. Anoverage is added to each syringe to account for the gel that is retainedin the syringe after dosing. This overage remains consistent at 23 μl,regardless of volume of gel in the syringe.

4.0% and 4.5% Intranasal Testosterone Compositions

TABLE 1 Components, Quantity, Quality Standards and Function—4.0%testosterone gel formulation of the invention Amount Amount perDelivered Amount Syringe per Dose Quality Component (% w/w) (mg) (mg)Function Standard Testosterone 4.0% 5.92 5.0 Active USP ingredientCastor oil 88.0%  130.24 110 Solvent USP Oleoyl 4.0% 5.92 5.0 Wettingagent Ph. Eur. macrogol- (hydrophilic glycerides oil) Colloidal 4.0%5.92 5.0 Viscosity USP/NF silicon increasing dioxide agent

TABLE 1A Components, Quantity, Quality Standards and Function—0.6%testosterone gel formulation of the invention Amount Amount perDelivered Amount Syringe per Dose Quality Component (% w/w) (mg) (mg)Function Standard Testosterone  0.6% 0.74 0.6 Active USP ingredientCastor oil 91.4%  112.42 91.4 Solvent USP Oleoyl  4.0% 4.92 4.0 Wettingagent Ph. polyoxyl- (hydrophilic Eur/NF. glycerides oil) Colloidal  4.0%4.92 4.0 Viscosity NF silicon increasing dioxide agent Total 100% 123 mg100 mg

TABLE 2 Components, Quantity, Quality Standards and Function, TBS-1: 5.6mg/125 μl/syringe (4.5% gel) Amount Amount per Delivered Amount Syringeper Quality Component (% w/w) (mg) Dose (mg) Function StandardTestosterone  4.5% 6.66 5.63 Active USP ingredient Castor oil 87.5%129.5 109.37 Solvent USP Oleoyl  4.0% 5.92 5.0 Wetting Ph. Eur.macrogol- agent glycerides (hydrophilic oil) Colloidal  4.0% 5.92 5.0Viscosity USP/NF silicon increasing dioxide agent

TABLE 3 Components, Quantity, Quality Standards and Function, TBS-1:6.75 mg/150 μl/syringe (4.5% gel) Amount Amount per Delivered AmountSyringe per Quality Component (% w/w) (mg) Dose (mg) Function StandardTestosterone 4.5% 7.79 6.75 Active USP ingredient Castor oil 87.5%151.37 131.25 Solvent USP Oleoyl 4.0% 6.92 6.0 Wetting Ph. Eur.macrogol- agent glycerides (hydrophilic oil) Colloidal 4.0% 6.92 6.0Viscosity USP/NF silicon increasing dioxide agentContainer

Testosterone gel formulations of the invention are supplied in unit-dosepolypropylene syringes. Two syringes of each dosage are packaged in aprotective aluminium foil pouch.

Example 2 Intranasal Testosterone Gel Formulations

The testosterone gel formulations of the invention are formulations oftestosterone in an intranasal gel proposed for assessing thepharmacokinetic of two different doses of testosterone gel formulationsof the invention for testosterone gel formulations of the invention inhypogonadal men.

The active ingredient, testosterone, is sourced from Bayer Schering.Challenges for nasal delivery include:

-   -   requirements for larger particles than pulmonary administration        (i.e., only particles >10 μm are sufficiently heavy to avoid        entering the respiratory tract);    -   concentrations must be higher due to the smaller volumes that        can be administered;    -   rapid clearance of the therapeutic agent from the site of        deposition results in a shorter time available for absorption;    -   potential for local tissue irritation; and    -   limited formulation manipulation possibilities to alter drug        delivery profiles.

Testosterone is indicated for TRT in males who are testosteronedeficient for any number of reasons, including hypogonadism. Thecurrently available options for administration of testosterone are oral,buccal, injectable, implantable and transdermal (patches and gels).

An intranasal testosterone (3.2%) gel is developed for the treatment ofhypogonadism in men and has been administered to hypogonadal men inseveral clinical trials, see e.g., Mattern, C. et al., 2008 The AgingMale 11(4):171-178 (December 2008, which is incorporated herein byreference in its entirety. In a phase II study NCT00975650, which wasperformed in the U.S. in testosterone deficient men and which wassupplemental to the Romanian study reported in Mattern et al., Supra,the 3.2% intranasal gel as reported in Mattern et al, Supra, failed toreach testosterone plasma levels required by the FDA to support TRTefficacy in testosterone deficient men. The intranasal testosterone gelsformulations of the present invention are developed at concentrations ofabout 4.0% and 4.5% testosterone.

Example 3 Overages Testosterone Gel Formulations of the Invention

No overage is added to the formulation. An overage is added to eachsyringe to account for the gel that is retained in the syringe afterdosing. This overage remains consistent at 23 μl, regardless of volumeof gel in the syringe. The theoretical fill and dispensed amounts fortestosterone gel formulations of the invention are provided below.

Theoretical Fill Theoretical Dispensed Syringe Dosage Volume (μl) Volume(μl) 4.0% Testosterone 148 125 Gel formulation of the Invention 4.5%Testosterone 148 125 Gel formulation of the Invention 4.5% Testosterone173 150 Gel formulation of the Invention

Example 4 Physicochemical and Biological Properties Testosterone GelFormulations of the Invention

The testosterone bio-adhesive gel formulations of the invention has aviscosity in the range of 3,000 to 10,000 mPa×sec. The viscosity isimportant because it facilitates maintenance of the gel in the nasalcavity in contact with the nasal mucosa. When the viscosity is less thanapproximately 3,000 mPa×sec (i.e., 3,000 centipoise), the gel tends tobe drawn by gravity out of the nasal cavity.

Example 5 Batch Formula Testosterone Gel Formulations of the Invention

Three different concentrations of testosterone gel formulations of theinvention, 0.15%, 0.45% and 0.6%, are manufactured for the proposedclinical trial. The batch formulae for these batches are presented inTable 5 below.

TABLE 5 200 KG Batch Formulae for 4.0% and 4.5% bio-adhesivetestosterone gel formulations of the invention at the 8 kg Batch SizeComponents 4.0% 4.5% Testosterone, USP  8 g  9 g Castor oil, USP 176 g175 g Oleoyl polyoxylglycerides, Ph.  8 g  8 g Eur./NF Colloidal silicondioxide, NF  8 g  8 g

Example 6

The Testosterone Gel Formulations of the Invention is manufacturedaccording to the process shown in FIG. 34 .

Mixing of the Ingredients—Bulk Gel

The Pre-Mix is prepared by mixing, with a propeller mixer, the fullamount of Testosterone with portion 1 of the castor oil for 10 minutes.

Mixture I is prepared by adding the Pre-Mix to the remaining castor oiland mixing for 60 minutes. The product temperature is maintained below50° C. for the entire mixing process.

The oleoyl polyxoylglycerides are pre-heated to 40-50° C. and mixed for10 minutes before being added to Mixture I. This is identified asMixture II. It is mixed for 45 minutes while maintaining producttemperature below 50° C. Mixture II is then screened through a sieve toremove any un-dissolved Testosterone aggregates.

Mixture III is prepared by adding the colloidal silicon dioxide toMixture II and mixing for 15 minutes while maintaining producttemperature below 50° C. A visual check is conducted after this step, toensure that the gel is clear.

At the completion of mixing the gel is stirred and cooled to a producttemperature below 30° C. The product is then discharged into stainlesssteel drums and the bulk gel sample is taken for analytical testing.

Filling and Packaging—Clinical Supplies

After release of the final gel mixture by the quality controllaboratory, the filling and packaging process is carried out by fillinga pre-determined volume into the syringe followed by the application ofthe syringe cap. Two syringes are packaged into a foil pouch.

The syringes are filled using a pipette with the gel taken from aholding tank. The tip of the pipette is discarded after the syringe isfilled and the syringe cap is applied. Each syringe is individuallylabeled.

Following the application of the label, two syringes are packaged in apre-formed foil pouch and the pouch is sealed. Each pouch is labelled.

Example 7 Drug Product TBS-1

The drug product, TBS-1, is a viscous and thixotropic, oil-basedformulation containing solubilized testosterone intended for intranasalapplication for the treatment of hypogonadism in men.

The drug product is formulated with the following compendial inactiveingredients: castor oil, oleoyl macrogolglycerides, and colloidalsilicon dioxide.

To allow for different doses to be administered in the Phase II program,a syringe is used as the unit dose container for the clinical supplies.

The syringes intended for use in the clinical program are needleless anda twist off cap is applied to the end of the syringe. The syringeconsists of the syringe barrel and the plunger. The syringe barrel isformed from polypropylene. The plunger is formed from polyethylene. Thesyringe cap is formed from High Density Polyethylene (HDPE).

New dose formulation of TBS-1 is manufactured for clinical studyTBS-1-2010-01 (submitted to the Agency on Jul. 28, 2010 Serial Number0019). The quantity of testosterone in these formulations is 4.0% and4.5% along with an adjustment of the amount of castor oil. The preciseformulation is listed in Tables 1, 2 and 3. TBS-1 is concentrated sothat the same dose is administered intranasally in a smaller volume.

Three different concentrations of TBS-1 gel will be administered in thisclinical trial 5.0 mg/125 μl/syringe (4.0% gel), 5.6 mg/125 μl/syringe(4.5% gel) and 6.75 mg/150 μl/syringe (4.5% gel). An overage is added toeach syringe to account for the gel that is retained in the syringeafter dosing. This overage remains consistent regardless of volume ofgel in the syringe.

Composition

The compositions of the three different concentrations of the drugproduct to be administered in this clinical trial are provided in Tables1, 2 and 3.

TABLE 1 Components, Quantity, Quality Standards and Function, TBS-1: 5.0mg/125 μl/syringe (4.0% gel) Amount Amount per Delivered Amount Syringeper Quality Component (% w/w) (mg) Dose (mg) Function StandardTestosterone  4.0% 2.92 5.0 Active USP ingredient Castor oil 88.0%130.24 110 Solvent USP Oleoyl  4.0% 5.92 5.0 Wetting Ph. Eur. macrogol-agent glycerides (hydrophilic oil) Colloidal  4.0% 5.92 5.0 ViscosityUSP/NF silicon increasing dioxide agent

TABLE 2 Components, Quantity, Quality Standards and Function, TBS-1: 5.6mg/125 μl/syringe (4.5% gel) Amount Amount per Delivered Amount Syringeper Quality Component (% w/w) (mg) Dose (mg) Function StandardTestosterone  4.5% 6.66 5.63 Active USP ingredient Castor oil 87.5%129.5 109.37 Solvent USP Oleoyl  4.0% 5.92 5.0 Wetting Ph. Eur.macrogol- agent glycerides (hydrophilic oil) Colloidal  4.0% 5.92 5.0Viscosity USP/NF silicon increasing dioxide agent

TABLE 3 Components, Quantity, Quality Standards and Function, TBS-1:6.75 mg/150 μl/syringe (4.5% gel) Amount Amount per Delivered AmountSyringe per Quality Component (% w/w) (mg) Dose (mg) Function StandardTestosterone 4.5% 7.79 6.75 Active USP ingredient Castor oil 87.5%151.37 131.25 Solvent USP Oleoyl 4.0% 6.92 6.0 Wetting Ph. Eur.macrogol- agent glycerides (hydrophilic oil) Colloidal 4.0% 6.92 6.0Viscosity USP/NF silicon increasing dioxide agentContainer

TBS-1 gel is supplied in unit-dose polypropylene syringes. Two syringesof each dosage are packaged in a protective aluminium foil pouch.

Control of Drug Products [TBS-1, Gel]

Specification [TBS-1, Gel]

The TBS-1 bulk gel is tested to the following specifications for batchrelease.

TABLE 1 Specification for TBS-1 Bulk Gel Test Parameter Method/ReferenceAcceptance Criteria Appearance Visually Slightly yellowish gel Colour ofAPHA colour reference Colour ≤ 250 formulation solution ViscosityRotational viscosimeter 3,000-10,000 mPa × sec USP <911> DensityRelative density 0.97-1.01 g/cm³ USP <699> Identification HPLC USP <621>Retention time corresponds to reference sample UV USP <197U> UV spectrumcorresponds to reference sample Impurities HPLC USP <621> Impurity C -Epitestosterone ≤ 0.5% Impurity I - Δ-6-testosterone ≤ 0.2% Eachindividual unknown impurity ≤ 0.1% Total impurities ≤ 1.0% Assay HPLCUSP <621> 95-105%

Finished product TBS-1 gel packaged in unit dose syringes is tested tothe following specifications for batch release.

TABLE 2 Specification for TBS-1 Gel Packaged in Unit Dose Syringes TestParameter Method/Reference Acceptance Criteria Appearance VisuallySlightly yellowish gel Identification HPLC USP <621> Retention timecorresponds to reference sample UV USP <197U> UV spectrum corresponds toreference sample Impurities HPLC USP <621> Impurity C - Epitestosterone≤ 0.5% Impurity I - Δ-6-testosterone ≤ 0.2% Each individual unknownimpurity ≤ 0.1% Total impurities ≤ 1.0% Assay HPLC USP <621> 95-105%Microbial limits USP <61> and <62> TAMC <10² cfu/g  TYMC <10 cfu/g P.aeruginosa 0/g S. aureus 0/g Mass variation USP <905> Complies with USP<905> TAMC—total aerobic microbial count TYMC—total combined yeast/mouldcount

Batch Analyses [TBS-1, Gel]

One preliminary batch (Batch No. 100304), four pilot scale batches(Batch No. ED 187, ED 188, ED 189 and ED 014), two pilot non-GMP batches(NA 090811-1 and NA090723-1) and three commercial scale (Batch 9256,0823 and 0743) batches of TBS-1 have been produced. Data from the newbatches, 0823 and 0743 are described in Tables 4 and 5.

TABLE 3 Description of TBS-1 Batches Formulation 4.0% 4.5% Batch no.0823 0743 Batch size 200 kg 200 kg Date of manufacture June 2010 June2010 Manufacturing site Haupt Pharma Haupt Pharma Batch no. testosterone89100760 89100760 (Bayer/Schering) (Bayer/Schering) Equipment CommercialProcess Commercial Process Filling quantity per 148 □g 173 □g container

Batch 0743, bulk 4.5% testosterone gel, is filled into two differentdosage strengths, 5.6 mg (Batch 0943) and 6.75 mg (Batch 0744), byvarying the weight of the gel in the finish syringe. Batch 0823, bulk4.0% testosterone gel, is filled as one dose strength, 5.0 mg (Batch0942).

TABLE 4 Batch Analysis - TBS-1 Batches 0743 and 0823 Test ParameterAcceptance Criteria Batch No. 0743 Batch No. 0823 Appearance of Clear,slightly yellowish Complies Complies formulation gel Colour ≤ APHAsolution 250 150 150 Viscosity 3,000-10,000 mPas/30 s 5,217 5,086Density 0.97-1.01 g/cm³ 0.99 0.99 Identification Retention time Complies5.0 Complies 5.0 corresponds to reference min min sample UV spectrumcorresponds Complies Complies to reference sample Impurities Imputity C-0.3 0.3 Epitestosterone ≤ 0.5% Impurity I Δ-6- <0.05 <0.05 testosterone≤ 0.2% Single impurity ≤ 0.1 <0.05 <0.05 Total impurities ≤ 1.0 0.5 0.5Assay 95.0-105.0% 100% 100% Microbial limits TAMC < 10² cfu/g  CompliesComplies TYMC < 10 cfu/g Complies Complies P. aeruginosa not detected/gComplies Complies S. aureus not detected/g Complies Complies TAMC—totalaerobic microbial count TYMC—total combined yeast/mould count

TABLE 5 Batch Analysis - TBS-1 Batches 00744, 0942 and 0943 TestAcceptance Parameter Criteria 0744 0942 0943 Batch No. 0743 0823 0743Bulk Appearance Slightly yellowish Complies Complies Complies gelIdentification Retention time Complies Complies Complies corresponds to4.9 min 5.0 min 4.9 min reference sample UV spectrum Complies CompliesComplies corresponds to reference sample Impurities Impurity C ≤    0.3%   0.3%    0.3% 0.5% Impurity I ≤ <0.05% <0.05% <0.05% 0.2% Eachindividual   0.05%   0.05%   0.05% unknown impurity ≤ 0.1% Totalimpurities ≤ 1.0%    0.3%    0.3%    0.3% Assay 95-105%     99%    100%   100% Microbial TAMC < 10² cfu/g  Complies Complies Complies limitsTYMC < 10 cfu/g Complies Complies Complies P. aeruginosa 0/g CompliesComplies Complies S. aureus 0/g Complies Complies Complies Mass Complieswith Complies Complies Complies variation USP <905>

Stability [TBS-1, Gel]

Stability Summary and Conclusions [TBS-1, Gel]

This section has been amended to include additional data on the on-goingstability studies for the initial stability batches and to providestability data on the drug product in the syringes utilized for thePhase II clinical study. Only the updated sections and new informationhave been included for review.

All stability studies of TBS-1 gel have been performed by ACC GmbHAnalytical Clinical Concepts, Schöntalweg 9-11, 63849Leidersbach/Aschaffenburg, Germany. Stability studies that meet ICHrequirements are on-going.

TABLE 1 Stability Studies Conducted in Support of TBS-1 ContainerStability Closure Drug Product Storage Data Study Study Type SystemBatch No. Conditions available End ICH White LDPE ED 187C 25° C./60% RH12 months Study unit dose ED 188 40° C./75% RH  6 months completedcontainer; ED 189 sterile air in ICH pressure EI 014 25° C./60% RH 36months Study cushion; plus a 42 completed aluminum month pouch analysissecondary ICH package (no ED 187B 9 hours ≥ 200 Full StudyPhotostability nitrogen) Wh/m² (300- exposure completed 400 nm) 22 hours1.2 Mill. Lxh. (400-800 nm) Thermal ED 188 12 hr −20° C. 4 weeks StudyCycling cycle to completed 12 hr + 40° C. ICH Syringe with Pilot Scale(non 25° C./60% RH 6 months Study Syringe Cap GMP) 40° C./75% RHcompleted 4.0 mg 5.5 mg 7.0 mg ICH Stainless 9256 Ambient 6 monthsOn-going Steel Drum temperature under Nitrogen ICH Syringe with Bulk9256 25° C./60% RH 6 months On-going Syringe Cap 9445 - 4.0 mg 40°C./75% RH 9246 - 5.5 mg 9247 - 7.0 mg ICH Stainless 0743 25° C./60% RHInitial Ongoing Steel Drum 0823 40° C./75% RH under Nitrogen ICH Syringewith 0943 25° C./60% RH initial Ongoing Syringe Cap 40° C./75% RH

Overall, stability data provided in this section are concluded tosupport a 24 month “use by” period for TBS-1 stored at controlled roomtemperature conditions [i.e., 25° C. (77° F.); excursions 15-30° C.(59-86° F.)]. The data also show that special storage conditions for thedrug product are not required. The packaging configuration is adequateto protect the drug product from light and the drug product does notdegrade or change physically following exposure to temperature cyclingstress.

The clinical supplies are applied a 1 year re-test period, when storedat controlled room temperature conditions [i.e., 25° C. (77° F.);excursions 15-30° C. (59-86° F.)], to reflect the duration of the trialand the data available. As additional data is available the re-testperiod will be extended as appropriate.

Stability Data [TBS-1, Gel]

In this section, the updated stability data tables for a commercial sizebulk Batch 9256, 0743 and 0823 and finish product lots 9445, 9446, 9447,0943 are provided.

A 6 month real time stability program is ongoing on the commercial scalebulk (Batch 9256). A 36 month real time and a 6 month acceleratedstability program is ongoing on three different doses of Batch 9256packaged in 1 ml syringes: Batch 9445 4.0 mg (3.2% gel), Batch 9446 5.5mg (3.2% gel), Batch 9447 7.0 mg (3.2% gel).

A 6 month real time stability program is underway on the commercialscale bulk batch 0743 (4.5% gel) and 0823 (4.0% gel). A 36 month realtime and a 6 month accelerated stability program is underway on Batch0943 (bulk Batch 0743 filled in 1 ml syringes).

TABLE 2 Stability Schedule for Commerical Scale Bulk TBS-1 gel andFinished Product Filled in 1 mL Syringes Storage Conditions CompletedTest Intervals (° C., % RH) Product (Outstanding Test Intervals) Ambienttemperature 9256 0 m, 3 m, 6 m 25 ± 2° C., 60 ± 5% 9445 0 m, 6 m (12 m,24 m, 36 m) 40 ± 2° C., 75 ± 5% 9445 0 m, 3 m, 6 m 25 ± 2° C., 60 ± 5%9446 0 m, 6 m (9 m, 18 m, 30 m, 36 m) 40 ± 2° C., 75 ± 5% 9446 0 m, 3 m,6 m 25 ± 2° C., 60 ± 5% 9447 0 m, 6 m, (12 m, 24 m, 36 m) 40 ± 2° C., 75± 5% 9447 0 m, 3 m, 6 m 25 ± 2° C., 60 ± 5% 0943 0 m, (3 m, 9 m, 18 m,30 m, 36 m) 40 ± 2° C., 75 ± 5% 0943 0 m, (3 m, 6 m) Ambient temperature0743 0 m, (3 m, 6 m) Ambient temperature 0823 0 m, (3 m, 6 m)

TABLE 3 Stability Data TBS-1 Batch 9256 (3.2% Bulk Gel) ManufacturedJuly 2009 Stored at Ambient Temperature Test 07/2009 10/2009 01/2010Parameter Acceptance Criteria Time 0 3 months 6 months AppearanceSlightly yellow gel Complies Complies Complies Colour of Colour ≤ 250200 200 200 formulation Viscosity 3,000-10,000 mPa × 5504 5325 5198 secDensity 0.97-1.01 g/cm³ 0.99 0.99 0.99 Iodine value FIPO 78.62 77.3976.40 Acid value FIPO ( mg KOH/g) 1.98 2.00 2.16 Peroxide FIPO (meqO₂/kg) 3.56 3.16 2.63 value Identification a. Retention time CompliesComplies Complies corresponds to RS b. UV spectrum Complies CompliesComplies corresponds to RS Impurities Imp C ≤ 0.5% 0.166% 0.148% 0.189%Imp I ≤ 0.1% <0.05%  0.05% <0.05% Each individual unknown  0.064%  0.05%0.075% imp. ≤ 0.1% Total imp. ≤ 1.0% 0.230% 0.198% 0.264% Imp. D ≤ 0.2% <0.2%  <0.2%  0.2% Assay 95.0-105%  99.4%  98.3% 100.4% Microbial TAMC<10² cfu/g  <10 cfu/g <10 cfu/g <10 cfu/g limits TYMC <10 cfu/g <10cfu/g <10 cfu/g <10 cfu/g S.aureus 0/g Not detected/g Not detected/g Notdetected/g P. aeruginosa 0/g Not detected/g Not detected/g Notdetected/g

TABLE 4 Stability Data 4.0 mg TBS-1 Batch 9445 (3.2% gel) 1 ml Syringe(25 ± 2° C., 60 ± 5% RH, horizontal) Test 6 12 Parameter AcceptanceCriteria Time 0 months months Appearance Slightly yellow gel CompliesColour of Colour ≤ 250 200 formulation Dissolution ≥80% within 120 min87.8% within 120 minutes Impurities Imp C ≤ 0.5% 0.127% Imp I ≤ 0.1%<0.05% Each individual <0.05% unknown imp. ≤ 0.1% Total imp. ≤ 1.0%0.127% Imp. D ≤ 0.2%  <0.2% Assay 95.0-105%  99.3% Microbial TAMC < 10²cfu/g <10 cfu/g limits TYMC < 10 cfu/g <10 cfu/g S. aureus 0/g Notdetected/g P. aeruginosa 0/g Not detected/g

TABLE 5 Stability Data 4.0 mg TBS-1 Batch 9445 (3.2% gel) 1 ml Syringe,(40 ± 2° C., 75 ± 5% RH, horizontal) Test Acceptance 3 6 ParameterCriteria Time 0 months months Appearance Slightly yellow gel CompliesComplies Colour of Colour ≤ 250 200 200 formulation Dissolution ≥80%within 87.8% within 87.3% within 120 min 120 minutes 120 minutesImpurities Imp C ≤ 0.5% 0.127% 0.128% Imp I ≤ 0.1% <0.05% <0.05% Eachindividual <0.05% Rel RT 0.38: unknown 0.177% imp. ≤ 0.1% Rel RT 2.93:0.066% Total imp. ≤ 1.0% 0.127% 0.371% Imp. D ≤ 0.2%  <0.2%  <0.2% Assay95.0-105%  99.3%  99.3% Microbial TAMC < 10² cfu/g <10 cfu/g <10 cfu/glimits TYMC < 10 cfu/g <10 cfu/g <10 cfu/g S. aureus 0/g Not detected/gNot detected/g P. aeruginosa 0/g Not detected/g Not detected/g

TABLE 6 Stability Data 5.5 mg TBS-1 Batch 9446 (3.2% gel) 1 ml Syringe,(25 ± 2° C., 60 ± 5% RH, horizontal) Test Acceptance 3 6 ParameterCriteria Time 0 months mos Appearance Slightly yellow gel CompliesComplies Colour of Colour ≤ 250 200 200 formulation Dissolution ≥80%within 86.8% within 83.6% within 120 min 120 minutes 120 minutesImpurities Imp C ≤ 0.5% 0.125% 0.126% Imp I ≤ 0.1% <0.05% <0.05% Eachindividual <0.05% <0.05% unknown imp. ≤ 0.1% Total imp. ≤ 1.0% 0.125%0.126% Imp. D ≤ 0.2%  <0.2%  <0.2% Assay 95.0-105%  99.1%  99.4%Microbial TAMC < 10² cfu/g <10 cfu/g <10 cfu/g limits TYMC < 10 cfu/g<10 cfu/g <10 cfu/g S. aureus 0/g Not detected/g Not detected/g P.aeruginosa 0/g Not detected/g Not detected/g

TABLE 7 Stability Data 5.5 mg TBS-1 Batch 9446 (3.2% gel) 1 ml Syringe,(40 ± 2° C., 75 ± 5% RH, horizontal) Test Acceptance 3 6 ParameterCriteria Time 0 months months Appearance Slightly yellow gel CompliesComplies Colour of Colour ≤ 250 200 200 formulation Dissolution ≥80%within 86.8% within 86.8% within 120 min 120 minutes 120 minutesImpurities Imp C ≤ 0.5% 0.125% 0.127% Imp I ≤ 0.1% <0.05% <0.05% Eachindividual <0.05% Rel RT 0.38: unknown 0.102% imp. ≤ 0.1% Rel RT 3.01:0.070 Total imp. ≤ 1.0% 0.125% 0.299% Imp. D ≤ 0.2%  <0.2%  <0.2% Assay95.0-105%  99.1%  97.9% Microbial TAMC < 10² cfu/g <10 cfu/g <10 cfu/glimits TYMC < 10 cfu/g <10 cfu/g <10 cfu/g S. aureus 0/g Not detected/gNot detected/g P. aeruginosa 0/g Not detected/g Not detected/g

TABLE 8 Stability Data 7.0 mg TBS-1 Batch 9447 (3.2% gel) 1 ml Syringe,(25 ± 2° C., 60 ± 5% RH, horizontal) Test 6 12 Parameter AcceptanceCriteria Time 0 months months Appearance Slightly yellow gel CompliesColour of Colour ≤ 250 200 formulation Dissolution ≥80% within 83.5%within 120 min 120 minutes Impurities Imp C ≤ 0.5% 0.132% Imp I ≤ 0.1%<0.05% Each individual <0.05% unknown imp. ≤ 0.1% Total imp. ≤ 1.0%0.132% Imp. D ≤ 0.2%  <0.2% Assay 95.0-105%  98.7% Microbial TAMC < 10²cfu/g <10 cfu/g limits TYMC < 10 cfu/g <10 cfu/g S. aureus 0/g Notdetected/g P. aeruginosa 0/g Not detected/g

TABLE 9 Stability Data 7.0 mg TBS-1 Batch 9447 (3.2% gel) 1 ml Syringe,(40 ± 2° C., 75 ± 5% RH., horizontal) Test Acceptance 3 6 ParameterCriteria Time 0 months months Appearance Slightly yellow gel CompliesComplies Colour of Colour ≤ 250 200 200 formulation Dissolution ≥80%within 83.5% within 85.4% within 120 min 120 minutes 120 minutesImpurities Imp C ≤ 0.5% 0.132% 0.132% Imp I ≤ 0.1% <0.05% <0.05% Eachindividual <0.05% Rel RT 0.37: unknown 0.074% imp. ≤ 0.1% Rel RT 3.13:0.069 Total imp. ≤ 1.0% 0.132% 0.275% Imp. D ≤ 0.2%  <0.2%  <0.2% Assay95.0-105%  98.7%  99.1% Microbial TAMC < 10² cfu/g <10 cfu/g <10 cfu/glimits TYMC < 10 cfu/g <10 cfu/g <10 cfu/g S. aureus 0/g Not detected/gNot detected/g P. aeruginosa 0/g Not detected/g Not detected/g

TABLE 10 Stability Data 5.6 mg TBS-1 Batch 0943 (4.5% gel) 1 ml Syringe,(25 ± 2° C., 60 ± 5% RH, horizontal) Test 3 6 Parameter AcceptanceCriteria Time 0 months months Appearance Slightly yellow gel CompliesColour of Colour ≤ 250 Complies formulation Impurities Imp C ≤ 0.5%   0.3% Imp I ≤ 0.1% <0.05% Each individual <0.05% unknown imp. ≤ 0.1%Total imp. ≤ 1.0% 0.3 Assay 95.0-105%    100% Microbial TAMC < 10² cfu/gComplies limits TYMC < 10 cfu/g Complies S. aureus 0/g Complies P.aeruginosa 0/g Complies

TABLE 11 Stability Data 5.6 mg TBS-1 Batch 0943 (4.5% gel) 1 ml Syringe,(40 ± 2° C., 75 ± 5% RH, horizontal) Test 3 6 Parameter AcceptanceCriteria Time 0 months months Appearance Slightly yellow gel CompliesColour of Colour ≤ 250 Complies formulation Impurities Imp C ≤ 0.5%   0.3% Imp I ≤ 0.1% <0.05% Each individual <0.05% unknown imp. ≤ 0.1%Total imp. ≤ 1.0% 0.3 Assay 95.0-105%    100% Microbial TAMC < 10² cfu/gComplies limits TYMC < 10 cfu/g Complies S. aureus 0/g Complies P.aeruginosa 0/g Complies

TABLE 12 Stability Data TBS-1 Batch 0743 (4.5% gel) Bulk Stored atAmbient Temperature Test 3 6 Parameter Acceptance Criteria Time 0 monthsmonths Appearance Slightly yellow gel Complies Colour of Colour ≤ 250Complies formulation Impurities Imp C ≤ 0.5%    0.3% Imp I ≤ 0.1% <0.05%Each individual <0.05% unknown imp. ≤ 0.1% Total imp. ≤ 1.0% 0.3 Assay95.0-105%    100% Microbial TAMC < 10² cfu/g Complies limits TYMC < 10cfu/g Complies S. aureus 0/g Complies P. aeruginosa 0/g Complies

TABLE 14 Stability Data TBS-1 Batch 0823 (4.5% gel) Bulk Stored atAmbient Temperature Test 3 6 Parameter Acceptance Criteria Time 0 monthsmonths Appearance Slightly yellow gel Complies Colour of Colour ≤ 250Complies formulation Impurities Imp C ≤ 0.5%    0.3% Imp I ≤ 0.1% <0.05%Each individual <0.05% unknown imp. ≤ 0.1% Total imp. ≤ 1.0% 0.3 Assay95.0-105%    100% Microbial TAMC < 10² cfu/g Complies limits TYMC < 10cfu/g Complies S. aureus 0/g Complies P. aeruginosa 0/g Complies

Example 8 Phase 2 Study Designed to Investigate the IntranasalAbsorption of 4% of the Drug Three Times a Day and 4.5% of the DrugAdministered Twice a Day and Three Times a Day

This is a Phase 2 study designed to investigate the intranasalabsorption of 4% of the drug three times a day and 4.5% of the drugadministered twice a day and three times a day, and to compare theabsorption from the previous study in the same subjects that respondedwith a 3.2% testosterone gel. In the previous study, Nasobol-01-2009, a3.2% Testosterone gel is used to deliver 4.0 mg, 5.5 mg and 7.0 mg ofTestosterone intra-nasally using gel volumes of 125 μL, 172 μL and 219μL, respectively. In this study, 5.0 mg, 5.65 mg and 6.75 mg ofTestosterone is administered in gel volumes of 125 μL, 125 μL, and 150μL, respectively. This study allowed investigating the delivery ofsimilar Testosterone amounts in much smaller volumes.

In this open label study, subjects are equally randomized into threetreatment arms. The treatments are administered for one week, in aparallel design. At the end of one week, the three treatments arecompared by conducting a 24-hour pharmacokinetic investigation of thesystemic absorption of the drug product testosterone and its twophysiological metabolites dihydrotestosterone and estradiol.

8. Study Objectives

8.1 Primary Objective

The primary objective of this study is to determine the bioavailabilitythrough PK analysis of a 4% TBS-1 gel (applied three times a day) and4.5% TBS-1 gel (applied twice a day and three times a day) inhypogonadal men.

8.2 Secondary Objective

The secondary objective of the study is to establish the safety profilefor TBS-1.

9. Investigational Plan

9.1 Overall Study Design and Plan Description

This is an open label, randomized, balanced, three treatment (4.0%t.i.d. 4.5% b.i.d. and 4.5% t.i.d.), parallel design, pharmacokineticstudy of TBS-1, administered intra-nasally. The serum concentrations oftotal Testosterone, Dihydrotestosterone and Estradiol are measured usingvalidated LC/MS methods.

Hypogonadal subjects are required to visit the Clinic on three (3)occasions, of which one (1) visit (Visit 3) required an overnight stayfor the previously described 24-hour pharmacokinetic profile.

The following pharmacokinetic parameters are determined for allsubjects:

-   -   AUC_(0-T), C_(avg), C_(min), C_(max), t_(max), PTF and PTS means        and standard error of the means are calculated for the 24-hour        interval.    -   The percentage of subjects with a C_(avg) for Testosterone,        Dihydrotestosterone and Estradiol, below, within and above the        Reference Range for the respective analyte is calculated.

Erythrocytosis, anemia and infections are monitored by measuringcomplete blood counts at screening and the Close-Out visit.

It is planned to enroll approximately 30 subjects. Twenty-two (22)subjects completed the study. Study participation is 2 to 3 weeks.

9.2 Discussion of Study Design

Testosterone therapy for hypogonadal men should correct the clinicalabnormalities of Testosterone deficiency, including disturbances ofsexual function. Testosterone decreases body fat and increases leanmuscle mass and bone density with minimal adverse effects.

There are several Testosterone replacement products available, which canbe given intra-muscularly, orally, as a buccal tablet to the gums, ortopically as a patch or gel. Current replacement therapies have certaindrawbacks. Testosterone injections show wide fluctuations in serumTestosterone levels often at values above the reference range (5).Testosterone patches have a high rate of skin irritation (6,7).Testosterone gels although popular in North America are not alwaysconvenient and have a risk of skin-to-skin transfer to family members(8,9). Oral Testosterone undecanoate needs to be administered with ahigh fat meal and levels obtained are often low (10-12).

Intra-nasal administration of a new formulation of Testosterone (TBS-1)has been shown to be effectively absorbed and shows excellent potentialas a therapeutic product in the treatment of male hypogonadism (13). Thenasal mucosa offers an alternative route of administration that is notsubject to the first pass effect, has high permeability and ease ofadministration with rapid absorption into the systemic circulationproducing high plasma levels similar to those observed after intravenousadministration.

The advantages of the Testosterone nasal gel, when compared to otherformulations, are the following: Convenient application form permittinginconspicuous use, the much smaller amount of active ingredient neededfor the subject, and knowing that this type of administration is lesslikely to contaminate other family members (wife and children).

Several studies have indicated the utility of testosteroneadministration using the nasal gel. The prior study conducted in 2009 isto demonstrate the efficacy of TBS-1 in the treatment of hypogonadal menrequiring Testosterone replacement therapy. Efficacy is determined byestablishing an optimal pharmacokinetic profile for serum Testosteronelevels following a multiple-dose b.i.d. dosing profile for TBS-1, usingthree different strengths of Testosterone (8.0 mg, 11.0 mg and 14.0 mg)and comparing it to that of the active control, Androderm®. Thesecondary objective of this study is to establish a safety profile forTBS-1. This is to be achieved by monitoring adverse and serious adverseevents during the course of the entire study, and comparing varioussafety parameters at follow-up to those obtained at baseline. Thesesafety parameters consisted of vital signs, complete blood counts, achemistry profile, an endocrine profile, and urinalysis. In addition,changes to the nasal mucosa and to the prostate at follow up arecompared to baseline.

An important advantage of the power of the dose finding design of thisstudy is that it minimizes the subject selection bias and the differenthost groups often observed in sequential study designs.

The three clinical sites are monitored by Schiff & Company to ensure thesafety of the Subjects and performance of the clinical study accordingto ICH E6 and FDA guidelines.

A central laboratory is used for the analysis of hematology andbiochemistry parameters in order to obtain consistent and unbiasedlaboratory results. A second central laboratory is used for the PKanalysis.

The following are the specific activities in the study design during thesubject visits:

In/Ex PERIOD Day 1 Day 7 Day 8 Visit Number: 1 2 3 PROCEDURE InformedConsent¹ x Medical History x Physical Exam* & Vital Signs x x x xSubject Demographic Data x x PROCEDURE Otorhinolaryngological Exam x xProstate Exam² x x Chemistry Profile³ x x Hematology Profile⁴ x xUrinalysis⁵ x x Serum PSA x x Hepatitis B, C, & HIV Testing x Urine DrugScreen⁶ x Ethanol Test⁷ x Hemoglobin A₁c x Serum Testosterone⁸ x SerumT, DHT & Estradiol x Serum T, DHT & Estradiol PK x ConcomitantMedications x x x x Adverse Event Recording x x x x *Physical Exam onScreen and Day 8 only. Informed consent will be signed prior toScreening Visit 1 In/Ex Period: Inclusion, and Exclusion Period ²Ifsubject had a prior normal prostate exam in Nasobol-01-2009, it will notbe required. ³Chemistry Profile: Na/K, Glucose, Urea, Creatinine, TotalBilirubin, Albumin, Calcium, Phosphate, Uric Acid, AST, ALT, ALP, GGTand CK. ⁴Complete Blood Count and Differential. ⁵Urine dipstick (nomicroscopic). ⁶Cocaine, Cannabinoids, Opiates, Benzodiazepines. ⁷Urinealcohol by dipstick. ⁸Serum Testosterone, Dihydrotestosterone &Estradiol will be measured by a reference lab using a validated LC-MS/MSmethod, for T and DHT and a validated LC-MS/MS or immunoassay method,for Estradiol.Screening Visit 1

-   -   Subjects, after having voluntarily signed the Informed Consent        Form, are interviewed by the Clinical Investigator or his/her        designee Physician/Nurse Practitioner who took the medical and        physical history, record demographic data, and performed a        routine physical examination. Body weight and Height is measured        and BMI calculated. Vital signs (seated 5 minutes) are measured        (Blood Pressure, Heart Rate, Respiratory Rate, and Body        Temperature).    -   If the subject had a normal digital rectal exam of the prostate        in the recent Nasobol-01-2009 trial, it is not repeated.    -   The Clinical Investigator assessed the subject study eligibility        based on the inclusion/exclusion criteria, and eligible subjects        that are currently on Testosterone replacement therapy needed to        undergo a wash-out period; four (4) weeks for depot products        administered intra-muscularly (e.g., Testosterone enanthate 200        mg/mL), and two (2) weeks for products administered orally or        topically (patch, gel, or buccal). At the end of the wash-out        period, subjects are to return to have their serum Testosterone        measured.    -   Treatment naïve subjects did not require a wash-out period.    -   Blood for serum Testosterone is drawn under fasting conditions,        at 0900 h±30 minutes. The serum Testosterone level must be >150        ng/dL, and <300 ng/dL.    -   Blood is drawn for Clinical Laboratory investigations after an        overnight fast (8-10 hour fast) and included the following:        -   Complete Blood Count (Hemoglobin, Hematocrit, MCV, MCHC,            RBC, WBC & Differential)        -   Clinical Chemistry profile (Na/K, Glucose, Urea, Creatinine,            Total Bilirubin, Albumin, Calcium, Phosphate, Uric Acid,            AST, ALT, ALP, GGT and CK)        -   Serum PSA        -   Testing for HBV, HCV and HIV (Hepatitis B surface antigen,            Hepatitis C antibody, HIV antibodies)        -   Whole blood sample for Hemoglobin A1c        -   Urine for dipstick urinalysis        -   Urine for Drug screen (Cocaine, Cannabis, Opiates and            Benzodiazepines). Subjects with positive test are not            enrolled, unless the positive test is due to interference            from a drug prescribed by a Physician        -   Urine for alcohol testing    -   The otorhinolaryngologic nasal endoscopy examination is done by        an ENT specialist.    -   Subjects that met all of the inclusion and exclusion criteria        are enrolled into the study and randomized into one of three        treatment groups (A, B or C).        Visit 2 (Day 1)    -   Subjects arrived at the Clinic under fasting conditions (6-8        hour fast) at 2000 hours or earlier.    -   Instructions are given to subjects on the proper technique for        intra-nasal dosing of TBS-1.    -   Blood is drawn at 2045 hours for baseline serum Testosterone,        Dihydrotestosterone, and Estradiol concentrations.    -   Vital Signs (seated 5 minutes) are measured (Blood Pressure,        Heart Rate, Respiratory Rate, and Body Temperature) to establish        a baseline.    -   Subjects are given a one week supply of pouches: 18 pouches for        treatment A, 12 pouches for treatment B, and 18 pouches for        treatment C. Pouches required for dosing during the        pharmacokinetic profile remained with the Clinical Investigator.        Each pouch contained two syringes pre-filled with TBS-1 gel for        treatment A, B, or C.    -   Subjects administered their first dose of TBS-1 at 2100 hours        according to their treatment group.    -   Vital Signs are measured at 2200 hours and subjects are sent        home with their supply of pouches for their treatment group.        Telephone Check (Day 4)

On Day 4, all subjects are called to check compliance of study drugadministration, compliance to abstention from alcohol for 48 hours, andto document any adverse events that may have occurred. Subjects arereminded to bring in all syringes for counting at Visit 3.

Visit 3 (Day 7)

-   -   Subjects arrived at the Clinic under fasting conditions (6-8        hour fast) at 2000 hours or earlier.    -   Blood is drawn at 2045 hours for baseline serum Testosterone,        Dihydrotestosterone, and Estradiol concentrations.    -   Subject underwent a 24-hour pharmacokinetic profile immediately        after the 2100 hour dosing. Vital signs are recorded hourly for        two hours post dosing.    -   Safety parameters are recorded.    -   Subjects remained fasting for two hours post dose and then given        supper. After supper, the subjects again fasted overnight and        remained fasting until 0900 hours on Day 8. Lunch and supper on        Day 8 occurred at the regular times and are not subject to        fasting conditions.        Pharmacokinetic Blood Draws    -   Administration of the drug should have occurred at ±5 minutes        from the indicated time (2100 h and 0700 h for b.i.d. dosing and        2100 h, 0700 h and 1300 h for t.i.d. dosing).    -   Blood draws should have been within ±5 minutes from the        indicated times when blood draw intervals are 30 minutes and        within ±15 minutes when blood draws are >30 minutes.    -   Treatment A: Blood draws for serum Testosterone,        Dihydrotestosterone, and Estradiol measurements: Blood draws for        t.i.d. dosing are done at the following times after the 2100        hour drug administration; 0.33, 0.66, 1.0, 1.5, 2.0, 3.0, 6.0,        9.0, 9.75, 10.33, 10.66, 11.0, 11.5, 12.0, 13.0, 14.0, 15.75,        16.33, 16.66, 17.0, 17.5, 18.0, 20.0, 22.0 and 24.0 hours,        (total blood draws; 25+baseline).    -   Treatment B: Blood draws for serum Testosterone,        Dihydrotestosterone, and Estradiol measurements: Blood draws for        b.i.d. dosing are done at the following times after the 2100        hour drug administration; 0.33, 0.66, 1.0, 1.5, 2.0, 3.0, 6.0,        9.0, 9.75, 10.33, 10.66, 11.0, 11.5, 12.0, 13.0, 16.0, 19.0,        22.0, and 24.0 hours, (total blood draws; 19+baseline).    -   Treatment C: Blood draws for serum Testosterone,        Dihydrotestosterone, and Estradiol measurements: Blood draws for        t.i.d. dosing are done at the following times after the 2100        hour drug administration; 0.33, 0.66, 1.0, 1.5, 2.0, 3.0, 6.0,        9.0, 9.75, 10.33, 10.66, 11.0, 11.5, 12.0, 13.0, 14.0, 15.75,        16.33, 16.66, 17.0, 17.5, 18.0, 20.0, 22.0 and 24.0 hours,        (total blood draws; 25+baseline).    -   The last blood draw in the pharmacokinetic profile included        enough blood to measure the clinical laboratory safety        parameters required at Close-out.        Visit 3 (Day 8), Close Out Visit        Subjects Underwent the Following Assessments:    -   A routine physical examination including vital signs (Blood        Pressure, Heart Rate, Respiratory Rate, and Body Temperature).    -   Otorhinolaryngologic nasal examination.    -   Blood sample is taken for a Complete Blood Count (Hemoglobin,        Hematocrit, RBC, WBC and differential, MCV, MCHC).    -   Blood sample for Chemistry Profile (Na/K, glucose, urea,        creatinine, calcium, phosphate, uric acid, total bilirubin,        albumin, AST, ALT, ALP, GGT, and CK).    -   Blood sample for PSA.    -   Urine sample for dipstick urinalysis.

9.3 Selection of Study Population

Subjects are included in the study according to the followinginclusion/exclusion criteria:

9.3.1 Inclusion Criteria

-   -   1. Males who are responders to high-dose intra-nasal        Testosterone in the Nasobol-01-2009 trial.    -   2. Written informed consent.    -   3. Males between 18 and 80 years of age.    -   4. Men with primary or secondary hypogonadism and a morning        (0900 h±30 minutes) serum Testosterone levels >150 ng/dL and        ≤300 ng/dL, on blood drawn under fasting conditions.    -   5. BMI between 18.5-35 kg/m².    -   6. All clinical laboratory assessments at the Screening Visit        are from blood drawn or urine collected following an overnight        fast (10 hours), and are within ±15% of the Clinical        Laboratory's reference range, except for serum Testosterone.    -   7. Normal Otorhinolaryngological nasal endoscopy examination.        See Appendix 16.1.1 for exclusion criteria pertaining to        endoscopy examination.    -   8. Prior, normal prostate examination (no palpable prostatic        mass) from the Nasobol-01-2009 trial.    -   9. A serum PSA≤4.0 ng/mL.

9.3.2 Exclusion Criteria

-   -   1. Significant inter-current disease of any type, in particular        liver, kidney, or heart disease, any form of diabetes mellitus        or psychiatric illness.    -   2. Limitations in mobility, defined as having difficulty walking        two blocks on a level surface or climbing 10 steps    -   3. Hematocrit >54% at screening.    -   4. History of cancer, excluding skin cancer.    -   5. History of nasal surgery, specifically turbinoplasty,        septoplasty, rhinoplasty, “nose job”, or sinus surgery.    -   6. Subject with prior nasal fractures.    -   7. Subject with active allergies, such as rhinitis, rhinorrhea,        and nasal congestion.    -   8. Subject with mucosal inflammatory disorders, specifically        pemphigus, and Sjogren's syndrome.    -   9. Subject with sinus disease, specifically acute sinusitis,        chronic sinusitis, or allergic fungal sinusitis.    -   10. History of nasal disorders (e.g., polyposis, recurrent        epistaxis (>1 nose bleed per month), abuse of nasal        decongestants) or sleep apnea.    -   11. Subject using any form of intra-nasal medication delivery,        specifically nasal corticosteroids and oxymetazoline containing        nasal sprays (e.g., Dristan 12-Hour Nasal Spray).    -   12. History of severe adverse drug reaction or leucopenia.    -   13. History of abnormal bleeding tendencies or thrombophlebitis        unrelated to venipuncture or intravenous cannulation.    -   14. Positive test for Hepatitis B, Hepatitis C, or HIV.    -   15. History of asthma and on-going asthma treatment.    -   16. History of sleeping problems.    -   17. Smokers (>10 cigarettes per day).    -   18. Regular drinkers of more than four (4) units of alcohol        daily (1 unit=300 mL beer, 1 glass wine, 1 measure spirit) or        those that may have difficulty in abstaining from alcohol during        the 48 hours prior to the 24-hour blood sampling visit.    -   19. History of, or current evidence of, abuse of alcohol or any        drug substance, licit or illicit; or positive urine drug and        alcohol screen for drugs of abuse and alcohol.    -   20. Current treatment with androgens (e.g.,        Dehydroepiandrostenedione, Androstenedione) or anabolic steroids        (e.g., Testosterone, Dihydrotestosterone).    -   21. Treatment with Estrogens, GnRH antagonists, or Growth        Hormone, within previous 12 months.    -   22. Treatment with drugs which interfere with the metabolism of        Testosterone, such as Anastrozole, Clomiphene, Dutasteride,        Finasteride, Flutamide, Ketoconazole, Spironolactone and        Testolactone.    -   23. Androgen treatment within the past four weeks        (intramuscular, topical, buccal, etc.).    -   24. Subject with poor compliance history or unlikely to maintain        attendance.    -   25. Participation in any other research study during the conduct        of this study or 30 days prior to the initiation of this study,        with the exception of Nasobol-01-2009.    -   26. Blood donation (usually 550 mL) at any time during this        study, and within the 12 week period before the start of this        study.

9.3.3 Removal of Subjects from Therapy or Assessment

Subjects are informed that they are free to withdraw from the study atany time without having to give reasons for their withdrawal, andwithout consequences for their future medical care. They are asked toinform the investigator immediately of their decision. The subject'sparticipation in the study may have been discontinued for any of thefollowing reasons:

-   -   Subject's own wish.    -   Significant non compliance with the study protocol and        procedures.    -   Inter-current illness which interferes with the progress of the        study.    -   Intolerable adverse event, including clinically significant        abnormal laboratory findings, where, in the opinion of the        Clinical Investigator, these could interfere with the subject's        safety.    -   Clinical Investigator's decision that the withdrawal from the        study is in the best interest of the subject.

The Clinical Investigator had the right to terminate a study prematurelyfor safety reasons, after having informed and consulted with theSponsor. The Sponsor had the right to terminate the study earlier if theclinical observations collected during the study suggested that it mightnot be justifiable to continue or for other reasons as described in thecontract between Sponsor and the clinical sites (e.g., administrative,regulatory, etc.). However this is not necessary. There are no prematureterminations or drops outs from the study.

9.4 Treatments

9.4.1 Treatments Administered

Subjects are centrally randomized to the following treatment groups inorder to balance the numbers equally within the groups across the threecenters:

-   -   Treatment A (n=10): TBS-1 syringes pre-filled with 125 μL 4.0%        gel to deliver 5.0 mg of Testosterone per nostril (intra-nasal)        given t.i.d. at 2100, 0700, and 1300 hours. (total dose 30        mg/day)    -   Treatment B (n=10): TBS-1 syringes pre-filled with 150 μL 4.5%        gel to deliver 6.75 mg of Testosterone per nostril (intra-nasal)        given b.i.d. at 2100 and 0700 hours. (total dose 27.0 mg/day)    -   Treatment C (n=10): TBS-1 syringes pre-filled with 125 μL 4.5%        gel to deliver 5.625 mg of Testosterone per nostril        (intra-nasal) given t.i.d. at 2100, 0700, and 1300 hours. (total        dose 33.75 mg/day)

9.4.2 Identity of Investigational Products

-   -   Name of the drug: TBS-1 (Syringes are pre-filled to contain 5.0        mg, 5.625 mg, and 6.75 mg of Testosterone/syringe).    -   Pharmaceutical form: Gel for nasal administration.    -   Content: Active ingredient: Testosterone.    -   Excipients: Silicon dioxide, castor oil, Labrafil®.    -   Mode of administration: Nasally, as a single dose to each        nostril.    -   Manufacturer: Haupt Pharma Amareg.    -   Batch numbers: 0744, 0942, and 0943    -   Storage conditions: Between 20-25° C.        Packaging        The TBS-1 study drug is delivered to the clinical trial site as        a ready-for-use syringe in a foil pouch (two syringes per        pouch). Examples of Syringe and Pouch Labels are described in        Appendix 4 of the protocol.        9.4.3 Method of Assigning Subjects to Treatment

Subjects who met the entry criteria are assigned randomly on a 1:1:1basis to one of the three treatment groups. At Screening, each subjectis assigned a subject number by site in sequential order. Subjectnumbers consisted of 5 digits. The first 2 digits reflected the sitenumber assigned to the investigator, followed by a 3-digit subjectnumber. For example, 01-001 indicates site (01) and the first subject(001). The subject number was used to identify the subject throughoutthe study and was entered on all documents. The same subject number wasnot assigned to more than one subject.

9.4.4 Selection of Doses in the Study

In a previous study, Nasobol-01-2009, a 3.2% Testosterone gel is used todeliver 4.0 mg, 5.5 mg and 7.0 mg of Testosterone intra-nasally usinggel volumes of 125 μL, 172 μL and 219 μL, respectively. In this study,5.0 mg, 5.65 mg and 6.75 mg of Testosterone are administered in gelvolumes of 125 μL, 125 μL, and 150 μL, respectively. This study permitsthe investigation of the delivery of similar Testosterone amounts inmuch smaller volumes.

9.4.5 Selection and Timing of Dose for Each Subject

This was based on the results of the prior study.

9.4.6 Blinding

There is no blinding, because this is an open label study. The rationalefor not blinding is that analytical endpoints, which are quantitativerather than qualitative are measured, and are not subject to any biasbeing introduced by the subjects or the Investigators.

9.4.7 Prior and Concomitant Therapy

The following medications are prohibited during the course of the study:

Subject using any form of intra-nasal medication delivery, specificallynasal corticosteroids and oxymetazoline containing nasal sprays (e.g.,Dristan 12-Hour Nasal Spray).

Current treatment with androgens (e.g., Dehydroepiandrostenedione,Androstenedione) or anabolic steroids (e.g., Testosterone,Dihydrotestosterone). Treatment with Estrogens, GnRH antagonists, orGrowth Hormone, within previous 12 months.

Treatment with drugs which interfere with the metabolism ofTestosterone, such as; Anastrozole, Clomiphene, Dutasteride,Finasteride, Flutamide, Ketoconazole, Spironolactone and Testolactone.

Androgen treatment within the past four weeks (intramuscular, topical,buccal, etc.).

9.4.8 Treatment Compliance

All drugs are dispensed in accordance with the protocol. It is thePrincipal Investigator's responsibility to ensure that an accuraterecord of drugs issues and return is maintained. At the end of thestudy, the used original packages are returned to the sponsor fordestruction. Drug accountability is verified by the monitors during thecourse of the study and prior to destruction of remaining study drugs.During Visit 2, the subjects are given a one-week supply of pouches; 18pouches for treatment A, 12 pouches for treatment B, and 18 pouches fortreatment C. Each pouch contained two syringes prefilled with TBS-onegel for treatment A, B, or C. The subjects are instructed on how toadminister the gel and are also given a diary to indicate the times ofadministration at their home.

9.5 Efficacy and Safety Variables

9.5.1 Efficacy and Safety Measurements Assessed

The primary efficacy parameter is the AUC is obtained in the 24 hourspost administration of TBS-1. From the AUC the 24 hour C_(avg) iscalculated.

-   -   Area under the concentration curve (AUC) for both b.i.d. and        t.i.d. dosing is determined for the 0 to 24 hour time interval        using the trapezoidal rule.    -   The average concentration in the dosing interval (C_(avg)) is        calculated from the AUC using the following formula:        C_(avg)=AUC_(0-T)/T, with T=dosing interval time.    -   Peak Trough Fluctuation (PTF) and Peak Trough Swing (PTS) is        calculated as follows:        PTF=(C _(max) −C _(min))/C _(avg)        PTS=(C _(max) −C _(min))/C _(min)    -   C_(min), C_(max) and t_(max) is taken from the actual measured        values. Values are determined relative to the Testosterone        administration time in treated subjects.    -   The percent of subjects with 24 hour C_(avg) values for serum        Testosterone, DHT and Estradiol concentration above, within, and        below the respective reference range are calculated.    -   Additional exploratory analyses of PK parameters may have been        performed as necessary.        Analysis of Safety Data

Erythrocytosis, anemia, and infections are monitored by measuringcomplete blood counts at screening, and the Close-Out visit. AnOtorhinolaryngological physician examined subjects and identifies anyclinically significant changes to the nasal mucosa at follow up comparedto baseline.

Clinical chemistry and urinalysis testing at Screening Visit 1 and atClose Out are assessed, hypo or hyperglycemia, renal function, liverfunction (hepato-cellular or obstructive liver disease), skeletal/heartmuscle damage, and changes in calcium homeostasis.

Serum PSA is measured as a cautionary measure to measure possiblechanges to the prostate, although changes to the prostate and to serumPSA is not expected in a short treatment time frame.

Measurement of serum Testosterone, Dihydrotestosterone and Estradiol, atScreening Visit 1 and Visit 3 permitted any excursions beyond the upperlimit of the reference range for the two physiological products ofTestosterone; DHT, and Estradiol to be observed.

The safety analysis is performed on all subjects who received TBS-1.Occurrence of adverse events are presented by treatment group, byseverity, and by relationship to the study drugs. All adverse events aredescribed and evaluated regarding causality and severity. Adverse eventsare classified using MedDRA. However they are very few and all but twoare not related to the drug.

Subject Safety

-   -   Monitoring of subjects and emergency procedures: Emergency        medication, equipment and Subject gurney are available at the        Study Center. During the “at home” phase, the subjects have an        emergency call number to be able to contact the Clinical        Investigator.    -   Adverse events are defined as any untoward medical occurrence in        a subject or clinical trial subject having administered a        medicinal product and which may or may not have a causal        relationship with this treatment. An adverse event can therefore        be any unfavorable and unintended sign, laboratory finding,        symptom or disease temporally associated with the use of an        investigational medicinal    -   product, whether considered related to it or not. Any        pre-existing condition during the clinical trial which is        worsened during the clinical study is to be considered an        adverse event.    -   An adverse reaction is defined as any untoward and unintended        response to an investigational product related to any dose        administered. All adverse reactions judged by either the        Clinical Investigator or the Sponsor to have reasonable causal        relationship to a medicinal product qualified as adverse        reactions. This is meant to convey in general that there is        evidence or an argument to suggest a causal relationship.    -   An unexpected adverse reaction is defined as an adverse        reaction, the nature, or severity of which is not consistent        with the applicable product information.    -   A serious adverse event or serious adverse reaction is defined        as any untoward medical occurrence or effect that, at any dose,        results in death, is life threatening, requires hospitalization        or prolongation of existing in-Subject hospitalization, results        in persistent or significant disability or incapacity, or is a        congenital anomaly or birth defect.    -   The observation period is extended from the time the subject        began the study medication through the end of Visit 3 for        hypogonadal subjects. AEs that are continuing at the end of the        study period are followed until the Investigator believed that        the AEs reached a stable clinical endpoint or are resolved.    -   The percent of subjects with a serum DHT and Estradiol greater        than the upper limit of the reference range, for the respective        analytes.    -   The Day 8 close-out findings are compared to the screening        results, and clinically significant changes identified in the        following:        -   Vital Signs and Adverse Events: Blood Pressure, Body            Temperature, Respiratory Rate, Heart Rate.        -   Otorhinolaryngological examination.        -   Complete Blood Count to evaluate changes in white blood            count, hemoglobin and hematocrit.        -   Clinical chemistry profile; Na/K, glucose, urea, creatinine,            calcium, phosphate, uric acid, total bilirubin, albumin,            AST, ALT, ALP, GGT, CK, and PSA.    -   Classifications:        -   A serious adverse event (SAE) or serious adverse reaction:            Defined as any untoward medical occurrence or effect that at            any dose; results in death, is life-threatening, requires            in-Subject hospitalization or prolongation of existing            in-Subject hospitalization, results in persistent or            significant disability or incapacity, is a congenital            anomaly or birth defect, a medically important condition,            i.e., the AE jeopardized the subject, or requires            intervention to prevent one of the outcomes listed above.        -   Non-serious AE: Any AE not meeting the SAE criteria.        -   Intensity: An adverse event/reaction is classified as Mild,            Moderate, or Severe.        -   Causality: The adverse event may be considered an adverse            reaction to an investigational medicinal product when a            “reasonable causal relationship” exists between the event            and the investigational product. The following degree of            causal relationship might be considered:            -   Definite: plausible temporal relationship with drug                administration and withdrawal, and re-appears after drug                re-start.            -   Probable: plausible temporal relationship with drug                administration.            -   Possible: plausible temporal relationship with drug                administration but can reasonably be associated to other                factors.            -   Unlikely: does not have plausible temporal relationship                with drug administration.            -   Unknown: no sufficient elements to establish a                correlation with drug intake.            -   Not Related: cannot be correlated to the drug                administration.    -   Procedure to be followed in the case of adverse events: All        adverse events detected by the Clinical Investigator are        recorded in the special section of the Case Report Form. Any        event that is classified as serious, regardless of causal        relationship, is to have been reported to the CRO and Sponsor        within 24 hours. There are no serious adverse events.

9.5.2 Appropriateness of Measurements

All measurements used in this study are standard indices of efficacy, PKand safety and are generally recognised as reliable, accurate andrelevant.

9.5.3. Primary Efficacy Variable(s)

Pharmacokinetic profiles of serum Testosterone for subjects dosed inTreatments A, B, and C that have:

-   -   1. A 24 hour C_(avg) value >300 ng/dL and <1050 ng/dL.    -   2. The percent of subjects in each treatment group with a 24        hour C_(avg) less than, within and above the serum Testosterone        reference range of 300 ng/dL-1050 ng/dL.

9.6 Data Quality Assurance

The CRF entries are verified by the monitors against source documents.All entries into the database included the CRF and Diary Card subjectdata, the PK results, and laboratory values. All data is 100% auditedafter being entered into the database for this report.

9.7 Statistical Methods Planned in the Protocol and Determination ofSample Size

9.7.1 Statistical and Analytical Plans

The PK Analysis Plan is described above. The Analysis Plan for the VitalSigns and Laboratory Results are compared baseline results with finalvisit results after PK analysis. Other data including demographic datais descriptive. No statistical analysis is performed because group sizesare not selected on the basis of statistical significance.

9.7.2 Determination of Sample Size

Based on the results are obtained from conducting severalpharmacokinetic studies in groups of 10 subjects per cohort, these aresufficient for an acceptable description of the pharmacokineticparameters in this population. As this is a relatively modest Phase IIPK study with the intent of investigating two higher concentrations ofTBS-1 gel, a true sample size calculation is not performed.

9.8 Changes in the Conduct of the Study or Planned Analysis

The protocol is amended on Jul. 27, 2010. The change requested is in thetiming of blood draws. The number of blood draws remained the same. Thischange is required to enable the full capture of the peak oftestosterone absorption following the third TID dosing which occurred at1300 hours on Day 8 or 1600 hours after the initial 2100 hour drugadministration on the previous day (Day 7).

10. Study Subjects

10.1 Disposition of Subjects

The study is conducted at three centers located in Miami, Fla.,Shreveport, L A and Tucson, Ariz.

The three treatment groups are equally divided amongst the three sites.Eight Subjects received Treatment A, seven Subjects received TreatmentsB and C, respectively. A total of 22 subjects are in the study. Inaddition, five subjects who participated in the previous clinical studyfailed screening and are therefore not randomized to the study.

TABLE 10.1 Disposition of Subjects by Site and Treatment Treatment A:Treatment B: Treatment C: TBS-1 syringe TBS-1 syringe TBS-1 syringeprefilled with prefilled with prefilled with SITE 125 micro-liters 150micro- 125 micro- ID of drug liters of drug liters of drug Total 01 3 33 9 02 3 2 2 7 03 2 2 2 6 Total 8 7 7 22

10.2 Protocol Deviations

There are no meaningful pharmacokinetic deviations.

11. Pharmacokinetics and Statistics

11.1 Datasets Analyzed

The PK population is defined as subjects who receive the Treatment A, Bor C, and who complete the study without major protocol violation or forwhom the PK profile can be adequately characterized. The PK populationis used for the analysis of PK data.

Based on the above criteria, twenty-two (22) subjects are included inthe PK population. The numbers of subjects by site and by treatment aredisplayed below.

TABLE 11.1.1 Disposition of Subjects in the PK population: Site Numberof Subjects 1 9 2 7 3 6 Treatment Number of Subjects A: TBS-1 125 μL of4.0% Gel (t.i.d.) 8 B: TBS-1 150 μL of 4.5% Gel (b.i.d.) 7 C: TBS-1 125μL of 4.5% Gel (t.i.d.) 711.2 Demographic and Other Baseline Characteristics

The demographic data and characteristics are presented by dose group forall the treated subjects in Table 11.2. No meaningful differences areobserved amongst the three groups for any of the characteristics.

TABLE 11.2 Summary of Demographic Characteristics-All Subjects TreatmentA: Treatment B: Treatment C: TBS-1 TBS-1 TBS-1 syringe syringe syringeprefilled with prefilled with prefilled with 125 micro- 150 micro- 125micro- liters of 4.0 liters of 4.5 liters of 4.5 All percent gel percentgel percent gel Subjects Characteristic (N = 8) (N = 7) (N = 7) (N = 22)SEX Male 8 7 7 22 RACE Black or 1 1 African American White 8 7 6 21ETHNIC Hispanic or 4 3 3 10 Latino Non-Hispanic 4 4 4 12 and Non-LatinoAGE Mean 52.38 53.86 51.57 52.59 SD 12.55 11.04 9.90 10.78 Minimum 37 3635 35 Maximum 73 63 67 73 Median 51 59 52 54

The treated populations for Group A have a mean age of 52.38, for GroupB 53.86, and for Group C 51.57. The standard deviations are 12.55,11.04, and 9.90, respectively. The ethnic and racial distribution areessentially the same in each group.

11.3 Measurement of Treatments Compliance

Compliance of drug utilization during the home portion of the study isdetermined by a review of the diaries and used returned pouches andsyringes. Although the method is not absolute, it is sufficient toestablish reasonable compliance. One subject could not find his diary.

11.4 Pharmacokinetics and Statistical Results

11.4.1 Methods

The blood concentrations are received from ABL and transferredelectronically from Trimel Biopharma SRL to the statistical unit ofPharmaNet. Testosterone and Dihydrotestosterone serum concentrations areprovided in ng/mL. However, the serum concentrations are converted tong/dL for PK calculation to match the units of the literature'sreference ranges.

During the trial, clinical site 1 performs PK sampling one day laterthan specified in the protocol that is it started on Day 8 rather thanDay 7. This change is not planned. Consequently, the actual times arecalculated relative to the 2100 drug administration on Day 8 for thesubjects of clinical site 1 and the drug administration 21 h00 on Day 7for the subjects of clinical sites 2 and 3.

For subject No. 02-003, the dosing time is not recorded on Day 7.Consequently, the schedule sampling times are used instead of the actualsampling times for PK calculations. The 16.33 h and 16.67 h samples forsubject 01-001 are drawn at the same time due to technical reason. Theschedule sampling time is used for sample 16.33 h while the actualsampling time is used for sample 16.67 h.

Excluding the above exceptions, time deviations during sampling aretreated as follows: for all sampling times, the difference between thescheduled and the actual sampling time is considered acceptable if it isless than 1 minute. When the difference exceeded this time limit, theactual sampling times (rounded off to three decimal digits) are used tocalculate pharmacokinetic parameters, except for pre-dose samples, whichare always reported as zero (0.000), regardless of time deviations.Scheduled sampling times are presented in concentration tables andgraphs in the statistical report.

PK calculations are performed using WinNonlin™ version 5.2 (or higher),validated according to industry's expectations and regulatoryrequirements. Descriptive statistical calculations are also performedusing Microsoft® Office Excel 2003. Microsoft® Office Excel 2003 andMicrosoft® Office Word 2003 are used for report data tabulation.

Descriptive statistics (N, mean, standard deviation (SD), coefficient ofvariation (CV), median, minimum value (Min.), and maximum value (Min.))of the serum concentrations versus time as well as all pharmacokineticparameters are provided for each treatment at each dose level using theevaluable population. All figures are presented using both linear (a)and semi-log (b) scales.

For the calculation of the PK parameters from the last three drugadministrations (Treatments A and C: 0 hour to 10 hours, 10 hours and 16hours and 16 hours and 24 hours; treatment B: 0 hour to 10 hours and 10hours and 24 hours), the serum concentration values for Testosterone,Dihydrotestosterone, and Estradiol at time points 10 hours (pre-dose forthe second drug administration) and 16 hours (pre-dose for the thirddrug administration under Treatments A and C) are obtained by imputingthe serum concentration value observed at time points 9.75 hours and15.75 hours, respectively.

The following pharmacokinetic parameters are determined for all subjectsfor Testosterone, Dihydrotestosterone and Estradiol:

For Treatments A and C (t.i.d.): AUC_(0-T), AUC₀₋₁₀, AUC₁₀₋₁₆, AUC₁₆₋₂₄,C_(max), C_(max 0-10), C_(max 10-16), C_(max 16-24), C_(min),C_(min 0-10), C_(min 10-16), C_(min 16-24), C_(avg), C_(avg 0-10),C_(avg 10-16), C_(avg 16-24), t_(max), t_(max 0-10), t_(max 10-16),t_(max 16-24), t_(max 10-24), PTF, PTS.

For Treatment B (b.i.d.): AUC_(0-T), AUC₀₋₁₀, AUC₁₀₋₂₄, C_(max),C_(max 0-10), C_(max 10-24), C_(min), C_(min 0-10), C_(min 10-24),C_(avg), C_(avg 0-10), C_(avg 10-24), t_(max), t_(max 0-10),t_(max 10-24), PTF, PTS.

Additionally, the percent of subjects with C_(avg) values for serumTestosterone, Dihydrotestosterone and Estradiol above, within, and belowtheir respective reference range is calculated for each treatment. Aswell, the mean percent time of serum Testosterone, Dihydrotestosteroneand Estradiol values above (% TimeAbove), within (% TimeWithin), andbelow (% TimeBelow) the corresponding reference range are provided foreach treatment. The calculation of all these pharmacokinetic parametersis explained below.

11.4.1.1 Maximum and Minimum Observed Concentrations and Time ofObserved Peak Concentrations

C_(max), the maximum is observed concentrations and T_(max), the time toreach that peak concentrations, as well as C_(min), the minimum observedconcentrations are determined for each subject and for each treatment asfollow:

-   -   C_(max): Maximum observed concentration over the dosing        interval. This parameter is calculated for Treatments A, B and        C.    -   C_(max 0-10): Maximum observed concentration from time zero to        10 hours. This parameter is calculated for Treatments A, B and        C.    -   C_(max 10-16): Maximum observed concentration from time 10 hours        to 16 hours. This parameter is calculated for Treatments A and        C.    -   C_(max 16-24): Maximum observed concentration from time 16 hours        to 24 hours. This parameter is calculated for Treatments A and        C.    -   C_(max 10-24): Maximum observed concentration from time 10 hours        to 24 hours. This parameter is calculated for Treatment B only.    -   C_(min): Minimum observed concentration over the dosing        interval. This parameter is calculated for Treatments A, B and        C.    -   C_(min 0-10): Minimum observed concentration from time zero to        10 hours. This parameter is calculated for Treatments A, B and        C.    -   C_(min 10-16): Minimum observed concentration from time 10 hours        to 16 hours. This parameter is calculated for Treatments A and        C.    -   C_(min 16-24): Minimum observed concentration from time 16 hours        to 24 hours. This parameter is calculated for Treatments A and        C.    -   C_(min 10-24): Minimum observed concentration from time 10 hours        to 24 hours. This parameter is calculated for Treatment B only.    -   t_(max): Time of observed C_(max) over the dosing interval. This        parameter is calculated for Treatments A, B and C.    -   t_(max 0-10): Time of observed C_(max) from time zero to 10        hours. This parameter is calculated for Treatments A, B and C.    -   t_(max 10-16): Time of observed C_(max) from time 10 hours to 16        hours. This parameter is calculated for Treatments A and C.    -   t_(max 16-24): Time of observed C_(max) from time 16 hours to 24        hours. This parameter is calculated for Treatments A and C.    -   t_(max 10-24): Time of observed C_(max) from time 10 hours to 24        hours. This parameter is calculated for Treatment B only.

11.4.1.2 Areas Under the Concentration-Time Curves

The calculation of AUCs is performed using the linear trapezoidalmethod. AUC_(0-T) is computed from dose time (0) to dose time □ (□=24h). However, in case the 24-h sample is collected with a time deviation,the AUC₀₋T is estimated based on the estimated concentration at 24 hoursusing the regression line calculated from the elimination phase, and notthe concentration at the actual observation time.

In the case where the last concentration value (Y) is missing or doesnot correspond to a scheduled sampling time (i.e. 10 hours and 16hours), AUC_(X-Y) is extrapolated using the corresponding subject'selimination phase, if calculable.

The following AUCs are calculated:

-   -   AUC_(0-T): Area under the concentration-time curve for one        dosing interval. This parameter is calculated for Treatments A,        B and C.    -   AUC₀₋₁₀: Area under the concentration-time curve from time zero        to 10 hours. This parameter is calculated for Treatments A, B        and C.    -   AUC₁₀₋₁₆: Area under the concentration-time curve from time 10        hours to 16 hours. This parameter is calculated for Treatments A        and C.    -   AUC₁₆₋₂₄: Area under the concentration-time curve from time 16        hours to 24 hours. This parameter is calculated for Treatments A        and C.    -   AUC₁₀₋₂₄: Area under the concentration-time curve from time 10        hours to 24 hours. This parameter is calculated for Treatment B        only.        The C_(avg) are calculated as follow:    -   C_(avg): Average concentration during the dosing interval,        calculated as AUC₀-T/T (T=24 hours). This parameter is        calculated for Treatments A, B and C.    -   C_(avg 0-10): Average concentration from time zero to 10 hours,        calculated as AUC0-10/10. This parameter is calculated for        Treatments A, B and C.    -   C_(avg 10-16): Average concentration from time 10 hours to 16        hours, calculated as AUC10-16/6. This parameter is calculated        for Treatments A and C.    -   C_(avg 16-24): Average concentration from time 16 hours to 24        hours, calculated as AUC16-24/8. This parameter is calculated        for Treatments A and C.    -   C_(avg 10-24): Average concentration from time 10 hours to 24        hours, calculated as AUC10-24/14. This parameter is calculated        for Treatment B only.

11.4.1.3 Average Drug Concentrations

The C_(avg) are calculated as follow:

-   -   C_(avg): Average concentration during the dosing interval,        calculated as AUC0-T/T (τ=24 hours). This parameter is        calculated for Treatments A, B and C.    -   C_(avg 0-10): Average concentration from time zero to 10 hours,        calculated as AUC0-10/10. This parameter is calculated for        Treatments A, B and C.    -   C_(avg 10-16): Average concentration from time 10 hours to 16        hours, calculated as AUC10-16/6. This parameter is calculated        for Treatments A and C.    -   C_(avg 16-24): Average concentration from time 16 hours to 24        hours, calculated as AUC16-24/8. This parameter is calculated        for Treatments A and C.    -   C_(avg 10-24): Average concentration from time 10 hours to 24        hours, calculated as AUC10-24/14. This parameter is calculated        for Treatment B only.

11.4.1.4 Peak Trough Fluctuation and Peak Trough Swing

The peak trough fluctuation (PTF) and the Peak trough swing arecalculated as follow:

-   -   PTF: Peak trough fluctuation, calculated as        (C_(max)−C_(min))/C_(avg) This parameter is calculated for        Treatments A, B and C.    -   PTS: Peak trough swing, calculated as (C_(max)−C_(min))/C_(min).        This parameter is calculated for Treatments A, B and C.        11.4.1.5 Percent Time Above, within and Below the Reference        Range and Percent of a Subjects with C_(avg) Above, within and        Below the Reference Range

The percent times during which observations fall above (% TimeAbove),within (% TimeWithin), and below (% TimeBelow) the reference ranges arecomputed for each subject and treatment for the serum Testosterone,Dihydrotestosterone and Estradiol. The percent of subjects with C_(avg)values for serum Testosterone, Dihydrotestosterone and Estradiol above,within, and below their respective reference range is calculated foreach treatment. The reference ranges are 300 ng/dL to 1050 ng/dL forTestosterone, 25.5 ng/dL to 97.8 ng/dL for Dihydrotestosterone and 3pg/mL to 81 pg/mL for Estradiol.

-   -   PTS: Peak trough swing, calculated as (C_(max)−C_(min))/C_(min).        This parameter is calculated for Treatments A, B and C.

11.4.1.6 Statistical Analysis

Only descriptive statistics (N, mean, SD, CV, median, Min., and Max.)are calculated on the serum concentrations and the PK parameters foreach treatment. No inferential statistical analysis is performed.

11.4.2 Analysis of Pharmacokinetics and Statistical Issues

11.4.2.2 Handling of Missing Data

Samples that are not analyzed due to an insufficient volume (refer tothe bioanalytical report) are recorded as INV (Insufficient volume foranalysis) in the concentration tables.

These samples are set as missing for pharmacokinetic and statisticalanalyses. As the PK parameters could be estimated using the remainingdata points, subjects with missing data are kept in the pharmacokineticanalysis.

11.4.2.3 Pharmacokinetic Analysis

The following pharmacokinetic parameters are determined for all subjectsfor Testosterone, Dihydrotestosterone and Estradiol:

For Treatments A and C AUC_(0-T), AUC₀₋₁₀, AUC₁₀₋₁₆, AUC₁₆₋₂₄, C_(max),C_(max 0-10), C_(max 10-16), C_(max 16-24), C_(min), C_(min 0-10),C_(min 10-16), C_(min 16-24), C_(avg), C_(avg 0-10), C_(avg 10-16),C_(avg 16-24), t_(max), t_(max 0-10), t_(max 10-16), t_(max 16-24),t_(max 10-24), PTF, PTS.

For Treatment B (b.i.d.): AUC_(0-T), AUC₀₋₁₀, AUC₁₀₋₂₄, C_(max),C_(max 0-10), C_(max 10-24), C_(min), C_(min 0-10), C_(min 10-24),C_(avg), C_(avg 0-10), C_(avg 10-24), t_(max), t_(max 0-10),t_(max 10-24), PTF, PTS. Additionally, the percent of subjects withC_(avg) values for serum Testosterone, Dihydrotestosterone and Estradiolabove, within, and below their respective reference range is calculatedfor each treatment. As well, the mean percent time of serumTestosterone, Dihydrotestosterone and Estradiol values above (%TimeAbove), within (% TimeWithin), and below (% TimeBelow) thecorresponding reference range are provided for each treatment. Thecalculation of all these pharmacokinetic parameters is explained below.

With the exception of text Tables (numbered as 11.4.2.3-1 to 11.4.2.3-3)and text Figures (numbered as 11.4.2.3-1 to 11.4.2.3-3), all tables andfigures referred to in this section are displayed in sections 14.2.1 and14.2.2, respectively. For brevity, TBS-1 treatments are identified inthe text of the statistical report by their treatment code: A (125 μL of4% gel given t.i.d. for a total dose of 30 mg/day), B (150 μL of 4.5%gel is given b.i.d. for a total dose of 27.0 mg/day) and C (125 μL of4.5% gel given t.i.d. for a total dose of 33.75 mg/day).

Blood samples for pharmacokinetic analysis are collected prior and postthe 2100 hour drug administration on Day 7 at 0.333, 0.667, 1.00, 1.50,2.00, 3.00, 6.00, 9.00, 9.75, 10.33, 10.66, 11.0, 11.5, 12.0, 13.0,14.0, 15.75, 16.33, 16.66, 17.0, 17.5, 18.0, 20.0, 22.0, and 24.0 hoursfor Treatments A and C. Blood samples for pharmacokinetic analysis arecollected prior and post the 2100 hour drug administration on Day 7 at0.333, 0.667, 1.00, 1.50, 2.00, 3.00, 6.00, 9.00, 9.75, 10.33, 10.66,11.0, 11.5, 12.0, 13.0, 16.0, 19.0, 22.0, and 24.0 hours for TreatmentB. The actual sampling times is used for PK calculation are displayed inTables 14.2.1.22, 14.2.1.23 and 14.2.1.24 for Treatments A, B and C,respectively.

Testosterone

The Testosterone serum concentrations measured for each subject at eachsampling time appear in Tables 14.2.1.1, 14.2.1.2 and 14.2.1.3 accordingto treatment. The plots of the individual serum levels over the samplingperiod are presented using both linear (a) and semi-log (b) scales inFIGS. 14.2 .2.1 through 14.2.2.22. Lines for the minimum (300 ng/dL) andmaximum (1050 ng/dL) bound of the reference range for the testosteroneserum concentrations are also presented for information purposes. Aswell, a line for the average drug concentration (C_(avg)) during thedosing interval (τ=24 hours) is also presented on the individualprofiles.

The plots of the mean serum levels over the sampling period are alsopresented using both the linear (a) and semi-log (b) scales in FIGS.14.2 .2.23, 14.2.2.24 and 14.2.2.25 for Treatments A, B and C,respectively. The error bars on these mean profiles correspond to onestandard deviation. The lines for the minimum and maximum bound of thereference ranges are also presented on the mean figures.

The mean plot on the linear scale for each treatment is also presentedbelow in the text FIG. 11.4 .2.3-1.

As shown in FIG. 35 the mean testosterone serum concentration (ng/dL)Time Profile for Each Treatment.

Calculated pharmacokinetic parameters for each subject according totreatment are shown in Tables 14.2.1.4, 14.2.1.5 and 14.2.1.6 forTreatments A, B and C, respectively. They are summarized in the textTable 11.4.2.3-1.

TABLE 11.4.2.3-1 Summary of Testosterone Pharmacokinetic Parameters forEach Treatment Treatment A¹ (N = 8) Treatment B² (N = 7) Treatment C³ (N= 7) Parameter Unit Mean SD CV % Mean SD CV % Mean SD CV % AUC₀₋₁₀ h *ng/dL 4178.68 1210.51 28.97 4451.64 1581.09 35.52 4355.19 1374.07 31.55C_(max 0-10) ng/dL 786 209 26.53 894 500 55.90 857 323 37.72C_(min 0-10) ng/dL 259 70.3 27.16 256 91.5 35.76 272 69.7 25.61C_(avg 0-10) ng/dL 418 121 28.97 445 158 35.52 436 137 31.55T_(max 0-10) h 1.01 0.678 67.21 0.695 0.279 40.18 0.905 0.422 46.62AUC₁₀₋₁₆ h * ng/dL 2635.05 1062.56 40.32 — — — 2301.51 658.44 28.61C_(max 10-16) ng/dL 698 251 35.88 — — — 675 256 37.98 C_(min 10-16)ng/dL 270 90.7 33.63 — — — 230 53.9 23.48 C_(avg 10-16) ng/dL 439 17740.32 — — — 384 110 28.61 T_(max 10-16) h 11.1 1.06 9.54 — — — 10.80.562 5.20 AUC₁₀₋₂₄ h * ng/dL — — — 5264.19 2176.63 41.35 — — —C_(max 10-24) ng/dL — — — 846 377 44.53 — — — C_(min 10-24) ng/dL — — —228 100 43.88 — — — C_(avg 10-24) ng/dL — — — 376 155 41.35 — — —T_(max 10-24) h — — — 11.1 0.675 6.06 — — — AUC₁₆₋₂₄ h * ng/dL 3016.521083.58 35.92 2766.97 838.13 30.29 C_(max 16-24) ng/dL 556 216 38.78 — —— 595 352 59.20 C_(min 16-24) ng/dL 271 86.9 32.08 — — — 225 59.1 26.26C_(avg 16-24) ng/dL 377 135 35.92 — — — 346 105 30.29 T_(max 16-24) h16.6 0.404 2.43 — — — 16.8 0.704 4.19 AUC₀₋— h * ng/dL 9920.07 3300.6533.27 9781.39 3532.43 36.11 9505.03 2650.59 27.89 C_(max) ng/dL 830 18822.65 1050 463 44.19 883 346 39.23 C_(min) ng/dL 239 77.6 32.55 224 98.643.97 222 57.1 25.69 C_(avg) ng/dL 413 138 33.27 408 147 36.11 396 11027.89 T_(max) h 4.61 5.27 114.31 4.99 5.43 108.81 4.50 6.44 143.18 PTF —1.51 0.39 26.03 2.04 1.07 52.23 1.61 0.47 28.92 PTS — 2.63 0.73 27.704.49 3.92 87.27 3.04 1.65 54.27 % % 34.47 30.93 89.72 36.40 25.92 71.2230.14 29.25 97.05 TimeBelow * % % 65.16 30.46 46.75 59.47 23.10 38.8468.21 28.77 42.17 TimeWithin % * % 0.38 1.06 282.84 4.13 6.88 166.671.65 2.60 157.31 TimeAbove C_(avg) Below * % 1 — — 1 — — 1 — — [N (% of(12.50%) (14.29%) (14.29%) Subjects) C_(avg) Within * % 7 — — 6 — — 6 —— [N (% of (87.50%) (85.71%) (85.71%) Subjects) C_(avg) Above * % 0 — —0 — — 0 — — [N (% of (0%)   (0%)   (0%)   Subjects)] *Reference Range =300-1050 ng/dL. ¹TBS-1, 125 μL 4.0% gel given t.i.d. (total dose 30mg/day) ²TBS-1, 150 μL of 4.5% gel given b.i.d. (total dose 27.0 mg/day)³TBS-1, 125 μL of 4.5% gel given t.i.d. (total dose 33.75 mg/day)

The percent times during which observations fall above (% TimeAbove),within (% TimeWithin), and below (% TimeBelow) the reference range arecomputed for each subject and are presented in Tables 14.2.1.4, 14.2.1.5and 14.2.1.6 for Treatments A, B and C, respectively. These results arealso summarized in text Table 11.4.2.3.1.

The percent of subjects with C_(avg) values for serum Testosteroneabove, within, and below the reference range is calculated for eachtreatment and are presented in Table 14.2.1.7. These results are alsosummarized in text Table 11.4.2.3.1.

Dihydrotestosterone

The Dihydrotestosterone serum concentrations are measured for eachsubject at each sampling time appear in Tables 14.2.1.8, 14.2.1.9 and14.2.1.10 according to treatment. The plots of the individual serumlevels over the sampling period are presented using both linear (a) andsemi-log (b) scales in FIGS. 14.2 .2.26 through 14.2.2.47. Lines for theminimum (25.5 ng/dL) and maximum (97.8 ng/dL) bound of the referencerange for the Dihydrotestosterone serum concentrations are alsopresented for information purposes. As well, a line for the average drugconcentration (C_(avg)) during the dosing interval (τ=24 hours) is alsopresented on the individual profiles.

The plots of the mean serum levels over the sampling period are alsopresented using both the linear (a) and semi-log (b) scales in FIGS.14.2 .2.48, 14.2.2.49 and 14.2.2.50 for Treatments A, B and C,respectively. The error bars on these mean profiles correspond to onestandard deviation. The lines for the minimum and maximum bound of thereference ranges are also presented on the mean figures.

The mean plot on the linear scale for each treatment is also presentedbelow in the text FIG. 11.4 .2.3-2.

As shown in FIG. 36 depicts the Mean Dihydrotestosterone SerumConcentration (ng/dL) Time Profile for Each Treatment is depicted.

As per SAP, AUC_(X-Y) is calculated based on the estimated concentration(Y) using the regression line calculated from the elimination phase datawhen the last concentration (Y) does not correspond to a schedulesampling time. For subject No. 01-002 and 02-007, the elimination phaseis not well characterized due to fluctuation in the Dihydrotestosteroneserum concentration for the 10 to 16 hours and 0 to 10 hours intervals,respectively. Therefore, AUC₁₀₋₁₆ and C_(avg 10-16) (derived fromAUC₁₀₋₁₆) could not be calculated for subject No. 01-002 for Treatment A(N=7 for these parameters). As well, AUC₀₋₁₀ and C_(avg 0-10) (derivedfrom AUC₀₋₁₀) could not be calculated for subject No. 02-007 forTreatment A (N=7 for these parameters).

Calculated pharmacokinetic parameters for each subject according totreatment are shown in Tables 14.2.1.11, 14.2.1.12 and 14.2.1.13 forTreatments A, B and C, respectively. They are summarized in the textTable 11.4.2.3-2.

TABLE 11.4.2.3-2 Summary of Dihydrotestosterone PharmacokineticParameters for Each Treatment Treatment A¹ Treatment B² Treatment C³ (N= 8) (N = 7) (N = 7) Parameter Unit Mean SD CV % Mean SD CV % Mean SD CV% AUC₀₋₁₀ ^(a) h * ng/dL 345.77 133.49 38.61 402.77 133.11 33.05 411.10131.22 31.92 C_(max 0-10) ng/dL 51.4 18.8 36.52 56.8 17.1 30.08 59.019.7 33.48 C_(min 0-10) ng/dL 26.6 10.1 38.15 30.1 13.4 44.57 31.7 9.3329.41 C_(avg 0-10) ^(a) ng/dL 34.6 13.3 38.61 40.3 13.3 33.05 41.1 13.131.92 T_(max 0-10) h 2.38 2.98 125.22 1.70 0.501 29.48 1.32 0.569 43.20AUC₁₀₋₁₆ ^(a) h * ng/dL 186.33 65.10 34.94 — — — 222.62 53.52 24.04C_(max 10-16) ng/dL 44.2 16.8 38.01 — — — 48.9 12.4 25.37 C_(min 10-16)ng/dL 26.6 10.4 38.95 — — — 30.1 8.41 27.94 C_(avg 10-16) ng/dL 31.110.8 34.94 — — — 37.1 8.92 24.04 T_(max 10-16) h 11.9 1.13 9.50 — — —11.4 0.436 3.84 AUC₁₀₋₂₄ h * ng/dL — — — 543.29 235.71 43.39 — — —C_(max 10-24) ng/dL — — — 54.6 21.9 40.12 — — — C_(min 10-24) ng/dL — —— 28.3 12.7 45.02 — — — C_(avg 10-24) ng/dL — — — 38.8 16.8 43.39 — — —T_(max 10-24) h — — — 11.8 0.775 6.55 — — — AUC₁₆₋₂₄ h * ng/dL 269.16114.13 42.40 — — — 275.21 74.02 26.89 C_(max 16-24) ng/dL 41.3 17.041.20 — — — 42.6 12.8 30.15 C_(min 16-24) ng/dL 26.5 11.3 42.63 — — —26.6 6.41 24.11 C_(avg 16-24) ng/dL 33.6 14.3 42.40 — — — 34.4 9.2526.89 T_(max 16-24) h 17.6 1.37 7.79 — — — 17.5 0.433 2.48 AUC_(0-τ) h *ng/dL 818.95 315.07 38.47 946.89 361.03 38.13 909.68 249.37 27.41C_(max) ng/dL 52.2 18.1 34.64 61.0 22.5 36.85 60.3 18.6 30.84 C_(min)ng/dL 25.3 10.1 40.14 27.8 13.0 46.69 26.6 6.41 24.11 C_(avg) ng/dL 34.113.1 38.47 39.5 15.0 38.13 37.9 10.4 27.41 T_(max) h 4.43 6.01 135.634.42 4.84 109.53 4.26 5.18 121.44 PTF — 0.82 0.28 34.18 0.89 0.33 36.710.88 0.17 19.17 PTS — 1.14 0.44 39.02 1.36 0.70 51.43 1.24 0.30 23.90 %TimeBelow * % 32.64 35.13 107.62 26.22 30.06 114.63 13.87 36.41 262.41 %TimeWithin * % 67.36 35.13 52.15 73.78 30.06 40.74 86.13 36.41 42.27 %TimeAbove * % 0.0 0.00 — 0.0 0.000 — 0.0 0.000 — C_(avg) Below * % 3 — —1 — — 1 — — [N (% of Subjects)] (37.50%) (14.29%) (14.29%) C_(avg)Within * 5 — — 6 — — 6 — — [N (% of Subjects)] % (62.50%) (85.71%)(85.71%) C_(avg) Above * % 0 — — 0 — — 0 — — [N (% of Subjects)] (0%)  (0%)   (0%)   *Reference Range = 25.5-97.8 ng/dL. ¹TBS-1, 125 μL 4.0%gel given t.i.d. (total dose 30 mg/day) ²TBS-1, 150 μL of 4.5% gel givenb.i.d. (total dose 27.0 mg/day) ³TBS-1, 125 μL of 4.5% gel given t.i.d.(total dose 33.75 mg/day) ^(a)For these parameters, N = 7 for TreatmentA.

The percent times during which observations fall above (% TimeAbove),within (% TimeWithin), and below (% TimeBelow) the reference range arecomputed for each subject and are presented in Tables 14.2.1.11,14.2.1.12 and 14.2.1.13 for Treatments A, B and C, respectively. Theseresults are also summarized in text Table 11.4.2.3.2. The percent ofsubjects with C_(avg) values for serum Dihydrotestosterone above,within, and below the reference range is calculated for each treatmentand are presented in Table 14.2.1.14. These results are also summarizedin text Table 11.4.2.3.2.

Estradiol

The Estradiol serum concentrations are measured for each subject at eachsampling time appear in Tables 14.2.1.15, 14.2.1.16 and 14.2.1.17according to treatment. The plots of the individual serum levels overthe sampling period are presented using both linear (a) and semi-log (b)scales in FIGS. 14.2 .2.51 through 14.2.2.72. Lines for the minimum (3pg/mL) and maximum (81 pg/mL) bound of the reference range for theEstradiol serum concentrations are also presented for informationpurposes. As well, a line for the average drug concentration (C_(avg))during the dosing interval (τ=24 hours) is also presented on theindividual profiles.

The plots of the mean serum levels over the sampling period are alsopresented using both the linear (a) and semi-log (b) scales in FIGS.14.2 .2.73, 14.2.2.74 and 14.2.2.75 for Treatments A, B and C,respectively. The error bars on these mean profiles correspond to onestandard deviation. The lines for the minimum and maximum bound of thereference ranges are also presented on the mean figures.

The mean plot on the linear scale for each treatment is also presentedbelow in the text FIG. 11.4 .2.3-3.

As shown in FIG. 37 the mean estradiol serum concentration (pg/mL) TimeProfile for Each Treatment is depicted.

As per SAP (section 8.3), AUC_(X-Y) is calculated based on the estimatedconcentration (Y) using the regression line calculated from theelimination phase data when the last concentration (Y) does notcorrespond to a schedule sampling time. However, for some subjects theelimination phase is not well characterized due to fluctuation in theEstradiol serum concentration as follows:

-   -   Subject No.: 02-007 for the 0 to 10 hours and for the 0 to 24        hours time intervals for Treatment A. The following PK        parameters could not be calculated for this subject: AUC₀₋₁₀,        C_(avg 0-10), AUC_(0-T), C_(avg) and PTF for Treatment A (N=7        for these parameters).    -   Subject Nos: 01-002 and 01-007 for the 10 to 16 hours time        interval for Treatment A. The AUC₁₀₋₁₆ and C_(avg 10-16) could        not be calculated for these subjects for Treatment A (N=6 for        these parameters).    -   Subject Nos. 02-004 and 02-007 for the 16 to 24 hours time        interval for Treatment A. The AUC₁₆₋₂₄ and C_(avg 16-24) could        not be calculated for this subject for Treatment A (N=6 for        these parameters).    -   Subject Nos. 02-003 and 02-005 for the 0 to 10 hours time        interval for Treatment C. The AUC₀₋₁₀ and C_(avg 0-10) could not        be calculated for these subjects for Treatment C (N=5 for these        parameters).

Calculated pharmacokinetic parameters for each subject according totreatment are shown in Tables 14.2.1.18, 14.2.1.19 and 14.2.1.20 forTreatments A, B and C, respectively. They are summarized in the textTable 11.4.2.3-3.

TABLE 11.4.2.3-3 Summary of Estradiol Pharmacokinetic Parameters forEach Treatment Treatment A¹ (N = 8) Treatment B² (N = 7) Treatment C³ (N= 7) Parameter Unit Mean SD CV % Mean SD CV % Mean SD CV % AUC₀₋₁₀^(b, c) h * pg/mL 234.96 95.96 40.84 242.02 64.26 26.55 267.78 75.3728.15 C_(max 0-10) pg/mL 36.8 13.4 36.33 35.8 9.06 25.29 35.5 7.75 21.80C_(min 0-10) pg/mL 17.7 6.43 36.35 17.4 5.67 32.63 22.1 8.07 36.43C_(avg 0-10) ^(b, c) pg/mL 23.5 9.60 40.84 24.2 6.43 26.55 26.8 7.5428.15 T_(max 0-10) h 2.62 2.87 109.67 1.49 0.608 40.85 2.68 3.38 126.14AUC₁₀₋₁₆ ^(d) h * pg/mL 144.76 51.60 35.65 — — — 144.30 53.70 37.21C_(max 10-16) pg/mL 28.9 10.8 37.29 — — — 31.5 8.82 28.02 C_(min 10-16)pg/mL 16.3 5.42 33.32 — — — 19.2 8.62 45.02 C_(avg 10-16) ^(d) pg/mL24.1 8.60 35.65 — — — 24.0 8.95 37.21 T_(max 10-16) h 12.1 1.15 9.49 — —— 11.2 0.693 6.19 AUC₁₀₋₂₄ h * pg/mL — — — 295.12 81.19 27.51 — — —C_(max 10-24) pg/mL — — — 30.6 8.16 26.70 — — — C_(min 10-24) pg/mL — —— 15.9 4.46 27.95 — — — C_(avg 10-24) pg/mL — — — 21.1 5.80 27.51 — — —T_(max 10-24) h — — — 12.4 1.74 14.00 — — — AUC₁₆₋₂₄ ^(d) h * pg/mL153.02 42.87 28.02 — — — 177.97 48.79 27.41 C_(max 16-24) pg/mL 27.210.4 38.23 — — — 26.9 7.99 29.74 C_(min 16-24) pg/mL 17.4 5.75 33.11 — —— 17.0 5.65 33.28 C_(avg 16-24) ^(d) pg/mL 19.1 5.36 28.02 — — — 22.26.10 27.41 T_(max 16-24) h 18.81 1.88 10.01 — — — 18.5 1.92 10.36AUC_(0-T) ^(b) h * pg/mL 530.27 196.8 37.12 537.16 137.99 25.69 601.91188.18 1.26 C_(max) pg/mL 37.9 13.6 35.97 36.2 8.69 24.04 36.4 8.4423.18 C_(min) pg/mL 16.1 5.36 33.31 15.7 4.40 28.03 17.0 5.65 33.28C_(avg) ^(b) pg/mL 22.1 8.20 37.12 22.4 5.75 25.69 25.1 7.84 31.26T_(max) h 4.13 7.13 172.74 4.51 5.25 116.25 4.88 5.27 107.94 PTF^(b) —0.97 0.35 36.08 0.93 0.28 30.25 0.81 0.21 25.16 PTS — 1.36 0.48 35.441.35 0.49 35.88 1.21 0.31 25.44 % % 0.00 0.00 — 0.00 0.00 — 0.00 0.00 —TimeBelow * % % 100.00 0.00 0.00 100.00 0.00 0.00 100.00 0.00 0.00TimeWithin * % % 0.00 0.00 — 0.00 0.00 — 0.00 0.00 — TimeAbove * C_(avg)Below ^(b,) * % 0 (0%) — — 0 (0%) — — 0 (0%) — — [N (% of Subjects)]C_(avg) Within ^(b,) * % 7 — — 7 — — 7 — — [N (% of (100.00%) (100.00%)(100.00%) Subjects)] C_(avg) % 0 (0%) — — 0 (0%) — — 0 (0%) — — Above^(b,) * [N (% of Subjects)] * Reference Range = 3-81 μg/mL. ¹TBS-1, 125μL 4.0% gel given t.i.d. (total dose 30 mg/day) ²TBS-1, 150 μL of 4.5%gel given b.i.d. (total dose 27.0 mg/day) ³TBS-1, 125 μL of 4.5% gelgiven t.i.d. (total dose 33.75 mg/day) ^(b)or these parameters, N = 7for Treatment A. ^(c)For these parameters, N = 6 for Treatment A.^(d)For these parameters, N = 5 for Treatment C.

The percent times during which observations fall above (% TimeAbove),within (% TimeWithin), and below (% TimeBelow) the reference range arecomputed for each subject and are presented in Tables 14.2.1.18,14.2.1.19 and 14.2.1.20 for Treatments A, B and C, respectively. Theseresults are also summarized in text Table 11.4.2.3.3.

The percent of subjects with C_(avg) values for serum Estradiol above,within, and below the reference range is calculated for each treatmentand are presented in Table 14.2.1.21. These results are also summarizedin text Table 11.4.2.3.3.

11.4.2.4 Pharmacodynamic Analysis

No pharmacodynamic analysis is planned or performed during this study.

11.4.7 Pharmacokinetic and Statistical Conclusions

In this Phase II study, subjects are randomized into three treatmentarms (4.0% TBS-1 administered t.i.d. and 4.5% TBS-1 administered bid.and t.i.d.). The treatments are administered for one week by intra-nasalroute, in a parallel design. At the end of one week, the threetreatments are compared by conducting a 24 hour pharmacokineticinvestigation of the systemic absorption of the drug productTestosterone, and its two physiological metabolites Dihydrotestosteroneand Estradiol.

Testosterone

The pharmacokinetic profile of TBS-1 following single and repeat dosingis examined in 2 previous studies (TST-PKP-01-MAT/04 andTST-DF-02-MAT/05). It is demonstrated in these studies that Testosteroneis well absorbed following intra-nasal administration. The maximal serumconcentration is reached after 1-2 hours post administration. In thecurrent study, the Testosterone formulations (4.0% TBS-1 is administeredt.i.d. and 4.5% TBS-1 is administered bid. and t.i.d.) are rapidlyabsorbed with a peak concentration reached within 36 minutes to 1 hour 6minutes (mean T_(max)) following intra-nasal administration. The maximumTestosterone concentration over the 24-hour interval is observed duringthe first administration (0-10 hours) in approximately 57% to 71% of thehypogonadal men while approximately 29% to 43% of the subjects had theirmaximum 24-h Testosterone concentration during the subsequentadministrations.

When TBS-1 administrations are compared separately for the t.i.d.treatments, although the mean AUC is similar between formulations, agreater AUC is observed following the first administration compared tothe two subsequent administrations (AUC₀₋₁₀: 4178.68 and 4355.19h*ng/dL>AUC₁₀₋₁₆: 2635.05 and 2301.51 h*ng/dL<AUC₁₆₋₂₄: 3016.52 and2766.97 h*ng/dL for Treatments A and C, respectively). A greater AUC isobserved for the second administration when compared to the firstadministration for Treatment B (AUC₀₋₁₀: 4451.64 h*ng/dL˜AUC₁₀₋₂₄:5264.19 h*ng/dL). The difference in AUC between administrations for boththe t.i.d. and b.i.d. formulations could be due to the different timeperiods elapsed between each administration. The mean AUC_(0-T)calculated over the 24-hour dosing interval, is comparable between alltreatments (AUC_(0-T): 9920.07, 9781.39 and 9505.03 h*ng/dL forTreatments A, B and C, respectively).

Although the mean C_(max) is similar between Treatments A and C, a trendtoward a decrease in C_(max) with subsequent administrations is observed(C_(max 0-10): 786 and 857 ng/dL>C_(max 10-16): 698 and 675ng/dL>C_(max 16-24): 556 and 595 ng/dL for Treatments A and C,respectively). Comparable mean Testosterone C_(max) is observed for bothadministrations of Treatment B (C_(max 0-10): 894 ng/dL˜C_(max 10-24):846 ng/dL). The difference in C_(max) between administrations for thet.i.d. formulations could be due to the different time periods that areelapsed between each administration. The mean C_(max) calculated overthe 24-hour dosing interval, is slightly greater for Treatment B (150 μLof 4.5% gel (b.i.d.)) (C_(max): 1050 ng/dL) comparatively to TreatmentsA and C (C_(max): 830 and 883 ng/dL, respectively). The upper limit ofthe physiological reference range (1050 ng/dL) is exceeded by 1 of 8subjects for Treatment A and 3 of 7 subjects for Treatments B and C.

A trend toward a slight decrease in C_(avg) is observed whenadministrations are compared separately for t.i.d. and b.i.d. treatments(C_(avg 0-10): 418 and 436 ng/dL>C_(avg 10-16): 439 and 384ng/dL>C_(avg 16-24): 377 and 346 ng/dL for Treatments A and C,respectively and C_(avg 0-10): 445 ng/dL>C_(avg 10-24): 376 ng/dL forTreatment B). The difference in C_(avg) between administrations could bedue to the different time periods that are elapsed between eachadministration. The mean C_(avg) calculated over the 24-hour dosinginterval, is comparable for all treatments (C_(avg): 413, 408, 396 ng/dLfor Treatments A, B and C, respectively).

These results suggest a decrease in exposure (AUC, C_(avg) and C_(max))between each dose for the t.i.d. administrations (Treatments A and C),but not for the b.i.d. administration (Treatment B). This decrease inexposure for the t.i.d. administrations could be partly explained by thenegative feedback on endogenous Testosterone production from the HPGaxis. In other words, due to the smaller time intervals between eachadministration for the t.i.d. groups, the recovery of the HPG systemfrom negative feedback would be less that for the b.i.d. group.

Independently of the formulation, approximately 86%-88% of the subjectshad an average drug concentration (C_(avg)) within the physiologicalreference range (300 to 1050 ng/dL), 13%-14% of the subjects had aC_(avg) below the reference range and no subjects had a C_(avg) abovethe reference range.

The period of time during a day (24 hours) for which serum Testosteroneconcentrations are below, within and above the physiological referencerange is covered respectively 30 to 35%, 59% to 68% and 0% of the24-hour period for all formulations. That is to say that thetestosterone levels are within normal range for about 14 to 16 hours aday.

Dihydrotestosterone

The Dihydrotestosterone peak concentration is reached within 1 hour 24minutes and 2 hours 23 minutes (mean T_(max)) following the TBS-1administrations. When TBS-1 administrations are compared separately forthe t.i.d. treatments, although the mean AUC is similar betweenformulations, a trend toward a decrease in AUC with subsequentadministrations is observed (AUC₀₋₁₀: 345.77 and 411.10h*ng/dL>AUC₁₀₋₁₆: 186.33 and 222.62 h*ng/dL>AUC₁₆₋₂₄: 269.16 and 275.21h*ng/dL for Treatments A and C, respectively). Comparable AUC isobserved for both administrations of Treatment B (AUC₀₋₁₀: 402.77h*ng/dL˜AUC₁₀₋₂₄: 543.29 h*ng/dL). The difference in AUC betweenadministrations for the t.i.d. formulations could be due to thedifferent time periods elapsed between each administration. The meanAUC_(0-T) calculated over the 24-hour dosing interval, is comparablebetween all treatments (AUC_(0-T): 818.95, 946.89 and 909.68 h*ng/dL forTreatments A, B and C, respectively).

Although the mean C_(max) is similar between the t.i.d. formulations, atrend toward a decrease in C_(max) with subsequent administrations isobserved (C_(max 0-10): 51.4 and 59.0 ng/dL>C_(max 10-16): 44.2 and 48.9ng/dL>C_(max 16-24): 41.3 and 42.6 ng/dL for Treatments A and C,respectively). Comparable mean Testosterone C_(max) is observed for bothadministrations of Treatment B (C_(max 0-10): 56.8 ng/dL˜C_(max 10-24):54.6 ng/dL). The difference in C_(max) between administrations for thet.i.d. formulations could be due to the different time periods elapsedbetween each administration. The mean C_(max) is calculated over the24-hour dosing interval, is comparable for all treatments (C_(max):52.2, 61.0 and 60.3 ng/dL for Treatments A, B and C, respectively). Theupper limit of the physiological reference range (97.8 ng/dL) is notexceeded by any subjects for any treatment.

The C_(avg) calculated by administration are comparable betweentreatments and administrations (C_(avg 0-10): 34.6 and 41.1ng/dL>C_(avg 10-16): 31.1 and 37.1 ng/dL>C_(avg 16-24): 33.6 and 34.4ng/dL for Treatments A and C, respectively and C_(avg 0-10): 40.3ng/dL>C_(avg 10-24): 38.8 ng/dL for Treatment B). The mean C_(avg)calculated over the 24-hour dosing interval, is comparable for alltreatments (C_(avg): 34.1, 39.5, 37.9 ng/dL for Treatments A, B and C,respectively).

Approximately 63% of subjects had their C_(avg) included in thephysiological reference range for DHT (25.5 to 97.8 ng/dL) followingadministration of Treatment A, whereas this number rises to about 86%when Treatments B and C are administered. No subject had their C_(avg)above the normal range while 38% and 14% of the subjects have theirC_(avg) below the normal range for Treatment A and both Treatments B andC, respectively.

The period of time during a day (24 hours) for which serum DHTconcentrations are below, within and above the physiological referencerange is covered respectively 32.64%, 67.36% and 0% for Treatment A,26.22%, 73.78% and 0% for Treatment B and 13.87%, 86.13% and 0% forTreatment C. That is to say that the DHT levels are within normal rangefor about 16, 18 and 21 hours a day for Treatments A, B and C,respectively.

Estradiol

The Estradiol peak concentration is reached within 1 hour 12 minutes and2 hours 41 minutes (mean T_(max)) following the TBS-1 administrations.

When TBS-1 administrations are compared separately for the t.i.d.treatments, although the mean AUC is similar between formulations, atrend toward a decrease in AUC with subsequent administrations isobserved (AUC₀₋₁₀: 234.96 and 267.78 h*pg/mL>AUC₁₀₋₁₆: 144.76 and 144.30h*pg/mL<AUC₁₆₋₂₄: 153.02 and 177.97 h*pg/mL for

Treatments A and C, respectively). Comparable AUC is observed for bothadministrations of Treatment B (AUC₀₋₁₀: 242.02 h*pg/mL˜AUC₁₀₋₂₄: 295.12h*pg/mL). The difference in AUC between administrations for the t.i.d.formulations could be due to the different time periods elapsed betweeneach administration. The mean AUC_(0-T) calculated over the 24-hourdosing interval, is comparable between all treatments (AUC_(0-T):530.27, 537.16 and 601.91 h*pg/mL for Treatments A, B and C,respectively).

Although the mean C_(max) is similar between the t.i.d. formulations, atrend toward a decrease in C_(max) with subsequent administrations isobserved (C_(max 0-10): 36.8 and 35.5 pg/mL>C_(max 10-16): 28.9 and 31.5pg/mL>C_(max 16-24): 27.2 and 26.9 pg/mL for Treatments A and C,respectively). Comparable mean Testosterone C_(max) is observed for bothadministrations of Treatment B (C_(max 0-10): 35.8 pg/mL˜C_(max 10-24):30.6 pg/mL). The difference in C_(max) between administrations for thet.i.d. formulations could be due to the different time periods elapsedbetween each administration. The mean C_(max) calculated over the24-hour dosing interval, is comparable for all treatments (C_(max):37.9, 36.2 and 36.4 pg/mL for Treatments A, B and C, respectively). Theupper limit of the physiological reference range (81 pg/mL) is notexceeded by any subjects for any treatment.

e C_(avg) calculated by administration are comparable between treatmentsand administrations (C_(avg 0-10): 23.5 and 26.8 pg/mL>C_(avg 10-16):24.1 and 24.0 pg/mL>C_(avg 16-24): 19.1 and 22.2 pg/mL for Treatments Aand C, respectively and C_(avg 0-10): 24.2 pg/mL>C_(avg 10-24): 21.1pg/mL for Treatment B). The mean C_(avg) is calculated over the 24-hourdosing interval, is comparable for all treatments (C_(avg): 22.1, 22.4,25.1 pg/mL for Treatments A, B and C, respectively).

All subjects have their C_(avg) included in the physiological referencerange for E₂ (3 to 81 pg/mL) following administration of all treatments.All subjects have E₂ concentrations within the normal range over the 24hours period. No subjects have E₂ levels below or above the normal rangeat any time of the day.

12. Safety Evaluation

12.1 Extent of Exposure

Subjects use the drug for 7 days at two sites and 8 days in another.

12.2 Adverse Events

12.2.1 Brief Summary of Adverse Events

There are eight adverse events that occurred in six subjects. Six of theevents occur during treatment A and two occur during treatment B.Subjects 01-002 and 01-007 both experience dizziness and both areindicated as possibly related to the study drug. Subject 01-002 hasmoderate severity which resolved after 5 days. Seven of the 8 adverseevents are mild. Six of the 8 events are not related to study drug.Individual 02-004 is classified as having anemia by the investigator.The hemoglobin is at the minimal normal level and is deemed unrelated tothe drug. Table 12.2.2 summarizes the events.

12.2.2 Display of Adverse Events

TABLE 12.2.2 Adverse Events Preferred Relation to Duration TreatmentSubject Age Term Severity Drug Start Date End Date (days) A 01-002 40Dizziness MODERATE POSSIBLY 2010 Oct. 25 2010 Oct. 30 5 RELATED A 01-00749 Dizziness MILD POSSIBLY 2010 Oct. 23 2010 Oct. 28 5 RELATED A 02-00453 Anemia MILD NOT 2010 Oct. 4 RELATED A 03-006 73 Pain of skin MILD NOT2010 Sep. 27 2010 Nov. 4 37 RELATED A 03-006 73 Excoriation MILD NOT2010 Sep. 2 2010 Nov. 4 62 RELATED A 03-006 73 Excoriation MILD NOT 2010Sep. 27 2010 Nov. 4 37 RELATED B 03-001 59 Respiratory MILD NOT 2010Sep. 5 2010 Sep. 13 8 tract RELATED congestion B 03-005 62Gastrooesopha- MILD NOT 2010 Sep. 14 2010 Sep. 27 13 geal reflux RELATEDdisease2.2.4 Listing of Adverse Events by Subjects

Table 12.2.2 list of adverse events by subject.

12.3 Deaths, Other Serious Adverse Events, and Other Significant AdverseEvents

There are no deaths, other serious adverse events or other significantadverse events during the course of this study.

12.4.2 Evaluation of Each Laboratory Parameter

There are no clinically significant changes in laboratory values fromthe beginning to the end of the study as determined by the principleinvestigators. All subjects did have some abnormal values at the initialvisit and/or at the third visit. There are no consistent changesthroughout the visits.

Subject 01-007 had a uric acid level of 539 U/L with 289 as the upperend of normal at the third visit. There are elevated glucose values inabout half the subjects compared to a normal first visit value. This isspread across all three dosages and are only slightly elevated. There isno clinical significance.

12.5 Vital Signs, Physical Findings, and Other Observations Related toSafety

There are no meaningful or significant changes in vital signs after testdrug administration.

12.6 Safety Conclusions

The TBS-1 gel demonstrates in this and other studies that it is safe foruse. There are no serious adverse events or any events of consequenceduring this PK study or during the seven days of self administration.Tables 14.3.2.1 through 14.3.2.8 show all the laboratory values forvisit 1 and visit 3.

13. Discussion and Overall Conclusions

The primary objective of this study is to determine the bioavailabilityof a 4.0% TBS-1 gel (applied t.i.d.) and 4.5% TBS-1 gel (applied b.i.d.and t.i.d.) in hypogonadal men.

In a previous study, Nasobol-01-2009, a 3.2% Testosterone gel is used todeliver 4.0 mg, 5.5 mg and 7.0 mg of Testosterone intra-nasally usinggel volumes of 125 μL, 172 μL and 219 μL, respectively. In this study,5.0 mg, 5.65 mg and 6.75 mg of Testosterone are administered in gelvolumes of 125 μL, 125 μL, and 150 μL, respectively. This study allowedinvestigating the delivery of similar Testosterone amounts in muchsmaller volumes.

The secondary objective of this study is to establish a safety profilefor TBS-1. In this Phase II study, subjects are randomized into threetreatment arms (4.0% TBS-1 administered t.i.d. and 4.5% TBS-1administered bid. and t.i.d.). The treatments are administered for oneweek by intra-nasal route, in a parallel design. At the end of one week,the three treatments are compared by conducting a 24 hourpharmacokinetic investigation of the systemic absorption of the drugproduct Testosterone, and its two physiological metabolitesDihydrotestosterone and Estradiol.

There are eight adverse events described by six subjects. Six of theevents occurred during treatment A and two occurred during treatment B.Subjects 01-002 and 01-007 both experienced dizziness and both areindicated as possibly related to the study drug. The remainder areunrelated to study drug.

There are no vital signs or laboratory changes that are significant ormeaningful. No erythrocytosis, anemia or infections are observed aftermeasurement of complete blood counts at screening and close-out.Clinical chemistry and urinalysis showed no changes at close-out in hypoor hyperglycemia, renal function, liver function, skeletal/heart muscledamage or changes in calcium homeostasis. There are no clinicallysignificant changes to the nasal mucosa.

The PK population is defined as subjects who received the Treatment A, Bor C, and who completed the study without major protocol violation orfor whom the PK profile can be adequately characterized. The PKpopulation is used for the analysis of PK data. Based on these criteria,twenty-two (22) subjects are included in the PK population.

Testosterone

The pharmacokinetic profile of TBS-1 following single and repeat dosingis examined in 2 previous studies (TST-PKP-01-MAT/04 andTST-DF-02-MAT/05). It is demonstrated in these studies that Testosteroneis well absorbed following intra-nasal administration. The maximal serumconcentration is reached after 1-2 hours post administration. In thecurrent study, the Testosterone formulations (4.0% TBS-1 administeredt.i.d. and 4.5% TBS-1 administered bid. and t.i.d.) are rapidly absorbedwith a peak concentration reached within 36 minutes to 1 hour 6 minutes(mean T_(max)) following intra-nasal administration. The maximumTestosterone concentration over the 24-hour interval is observed duringthe first administration (0-10 hours) in approximately 57% to 71% of thehypogonadal men while approximately 29% to 43% of the subjects had theirmaximum 24-h Testosterone concentration during the subsequentadministrations.

When TBS-1 administrations are compared separately for the t.i.d.treatments, although the mean AUC is similar between formulations, agreater AUC is observed following the first administration compared tothe two subsequent administrations (AUC₀₋₁₀: 4178.68 and 4355.19h*ng/dL>AUC₁₀₋₁₆: 2635.05 and 2301.51 h*ng/dL<AUC₁₆₋₂₄: 3016.52 and2766.97 h*ng/dL for Treatments A and C, respectively). A greater AUC isobserved for the second administration when compared to the firstadministration for Treatment B (AUC₀₋₁₀: 4451.64 h*ng/dL˜AUC₁₀₋₂₄:5264.19 h*ng/dL). The difference in AUC between administrations for boththe t.i.d. and b.i.d. formulations could be due to the different timeperiods elapsed between each administration. The mean AUC_(0-t)calculated over the 24-hour dosing interval, is comparable between alltreatments (AUC_(0-t): 9920.07, 9781.39 and 9505.03 h*ng/dL forTreatments A, B and C, respectively).

When TBS-1 administrations are compared separately for the t.i.d.treatments, although the mean C_(max) is similar between formulations, atrend toward a decrease in C_(max) with subsequent administrations isobserved (C_(max 0-10): 786 and 857 ng/dL>C_(max 10-16): 698 and 675ng/dL>C_(max 16-24): 556 and 595 ng/dL for Treatments A and C,respectively). Comparable mean Testosterone C_(max) is observed for bothadministrations of Treatment B (C_(max 0-10): 894 ng/dL˜C_(max 10-24):846 ng/dL). The difference in C_(max) between administrations for thet.i.d. formulations could be due to the different time periods elapsedbetween each administration. The mean C_(max) calculated over the24-hour dosing interval, is slightly greater for Treatment B (150 μL of4.5% gel (b.i.d.)) (C_(max): 1050 ng/dL) comparatively to Treatments Aand C (C_(max): 830 and 883 ng/dL, respectively). The upper limit of thephysiological reference range (1050 ng/dL) is exceeded by 1 of 8subjects for Treatment A and 3 of 7 subjects for Treatments B and C.

A trend toward a slight decrease in C_(avg) is observed whenadministrations are compared separately for t.i.d. and b.i.d. treatments(C_(avg 0-10): 418 and 436 ng/dL>C_(avg 10-16): 439 and 384ng/dL>C_(avg 16-24): 377 and 346 ng/dL for Treatments A and C,respectively and C_(avg 0-10): 445 ng/dL>C_(avg 10-24): 376 ng/dL forTreatment B). The difference in C_(avg) between administrations could bedue to the different time periods elapsed between each administration.The mean C_(avg) calculated over the 24-hour dosing interval, iscomparable for all treatments (C_(avg): 413, 408, 396 ng/dL forTreatments A, B and C, respectively).

These results suggest a decrease in exposure (AUC, C_(avg) and C_(max))between each dose for the t.i.d. administrations (Treatments A and C),but not for the b.i.d. administration (Treatment B). This decrease inexposure for the t.i.d. administrations could be partly explained by thenegative feedback on endogenous Testosterone production from the HPGaxis. In other words, due to the smaller time intervals between eachadministration for the t.i.d. groups, the recovery of the HPG systemfrom negative feedback would be less that for the b.i.d. group.

Independently of the formulation, approximately 86%-88% of the subjectshad an average drug concentration (C_(avg)) within the physiologicalreference range (300 to 1050 ng/dL), 13%-14% of the subjects had aC_(avg) below the reference range and no subjects had a C_(avg) abovethe reference range.

The period of time during a day (24 hours) for which serum Testosteroneconcentrations are below, within and above the physiological referencerange covered respectively 30 to 35%, 59% to 68% and 0% of the 24-hourperiod for all formulations. That is to say that the Testosterone levelsare within normal range for about 14 to 16 hours a day.

Dihydrotestosterone

The Dihydrotestosterone peak concentration is reached within 1 hour 24minutes and 2 hours 23 minutes (mean T_(max)) following the TBS-1administrations. When TBS-1 administrations are compared separately forthe t.i.d. treatments, although the mean AUC is similar betweenformulations, a trend toward a decrease in AUC with subsequentadministrations is observed (AUC₀₋₁₀: 345.77 and 411.10h*ng/dL>AUC₁₀₋₁₆: 186.33 and 222.62 h*ng/dL>AUC₁₆₋₂₄: 269.16 and 275.21h*ng/dL for Treatments A and C, respectively). Comparable AUC isobserved for both administrations of Treatment B (AUC₀₋₁₀: 402.77h*ng/dL˜AUC₁₀₋₂₄: 543.29 h*ng/dL). The difference in AUC betweenadministrations for the t.i.d. formulations could be due to thedifferent time periods elapsed between each administration. The meanAUC_(0-t) calculated over the 24-hour dosing interval, is comparablebetween all treatments (AUC_(0-t): 818.95, 946.89 and 909.68 h*ng/dL forTreatments A, B and C, respectively).

Although the mean C_(max) is similar between the t.i.d. formulations, atrend toward a decrease in C_(max) with subsequent administrations isobserved (C_(max 0-10): 51.4 and 59.0 ng/dL>C_(max 10-16): 44.2 and 48.9ng/dL>C_(max 16-24): 41.3 and 42.6 ng/dL for Treatments A and C,respectively). Comparable mean Testosterone C_(max) is observed for bothadministrations of Treatment B (C_(max 0-10): 56.8 ng/dL˜C_(max 10-24):54.6 ng/dL). The difference in C_(max) between administrations for thet.i.d. formulations could be due to the different time periods elapsedbetween each administration. The mean C_(max) calculated over the24-hour dosing interval, is comparable for all treatments (C_(max):52.2, 61.0 and 60.3 ng/dL for Treatments A, B and C, respectively). Theupper limit of the physiological reference range (97.8 ng/dL) is notexceeded by any subjects for any treatment.

The C_(avg) calculated by administration are comparable betweentreatments and administrations (C_(avg 0-10): 34.6 and 41.1ng/dL>C_(avg 10-16): 31.1 and 37.1 ng/dL>C_(avg 16-24): 33.6 and 34.4ng/dL for Treatments A and C, respectively and C_(avg 0-10): 40.3ng/dL>C_(avg 10-24): 38.8 ng/dL for Treatment B). The mean C_(avg)calculated over the 24-hour dosing interval, is comparable for alltreatments (C_(avg): 34.1, 39.5, 37.9 ng/dL for Treatments A, B and C,respectively).

Approximately 63% of subjects had their C_(avg) included in thephysiological reference range for DHT (25.5 to 97.8 ng/dL) followingadministration of Treatment A, whereas this number rises to about 86%when Treatments B and C are administered. No subject had their C_(avg)above the normal range while 38% and 14% of the subjects had theirC_(avg) below the normal range for Treatment A and both Treatments B andC, respectively.

The period of time during a day (24 hours) for which serum DHTconcentrations are below, within and above the physiological referencerange covered respectively 32.64%, 67.36% and 0% for Treatment A,26.22%, 73.78% and 0% for Treatment B and 13.87%, 86.13% and 0% forTreatment C. That is to say that the DHT levels are within normal rangefor about 16, 18 and 21 hours a day for Treatments A, B and C,respectively.

Estradiol

The Estradiol peak concentration is reached within 1 hour 12 minutes and2 hours 41 minutes (mean T_(max)) following the TBS-1 administrations.

When TBS-1 administrations are compared separately for the t.i.d.treatments, although the mean AUC is similar between formulations, atrend toward a decrease in

AUC with subsequent administrations is observed (AUC₀₋₁₀: 234.96 and267.78 h*pg/mL>AUC₁₀₋₁₆: 144.76 and 144.30 h*pg/mL<AUC₁₆₋₂₄: 153.02 and177.97 h*pg/mL for Treatments A and C, respectively). Comparable AUC isobserved for both administrations of Treatment B (AUC₀₋₁₀: 242.02h*pg/mL˜AUC₁₀₋₂₄: 295.12 h*pg/mL). The difference in AUC betweenadministrations for the t.i.d. formulations could be due to thedifferent time periods elapsed between each administration. The meanAUC_(0-t) calculated over the 24-hour dosing interval, is comparablebetween all treatments (AUC_(0-t): 530.27, 537.16 and 601.91 h*pg/mL forTreatments A, B and C, respectively).

Although the mean C_(max) is similar between the t.i.d. formulations, atrend toward a decrease in C_(max) with subsequent administrations isobserved (C_(max 0-10): 36.8 and 35.5 pg/mL>C_(max 10-16): 28.9 and 31.5pg/mL>C_(max 16-24): 27.2 and 26.9 pg/mL for Treatments A and C,respectively). Comparable mean Testosterone C_(max) is observed for bothadministrations of Treatment B (C_(max 0-10): 35.8 pg/mL˜C_(max 10-24):30.6 pg/mL). The difference in C_(max) between administrations for thet.i.d. formulations could be due to the different time periods elapsedbetween each administration. The mean C_(max) calculated over the24-hour dosing interval, is comparable for all treatments (C_(max):37.9, 36.2 and 36.4 pg/mL for Treatments A, B and C, respectively). Theupper limit of the physiological reference range (81 pg/mL) is notexceeded by any subjects for any treatment.

The C_(avg) calculated by administration are comparable betweentreatments and administrations (C_(avg 0-10): 23.5 and 26.8pg/mL>C_(avg 10-16): 24.1 and 24.0 pg/mL>C_(avg 16-24): 19.1 and 22.2pg/mL for Treatments A and C, respectively and C_(avg 0-10): 24.2pg/mL>C_(avg 10-24): 21.1 pg/mL for Treatment B). The mean C_(avg)calculated over the 24-hour dosing interval, is comparable for alltreatments (C_(avg): 22.1, 22.4, 25.1 pg/mL for Treatments A, B and C,respectively).

All subjects had their C_(avg) included in the physiological referencerange for E₂ (3 to 81 pg/mL) following administration of all treatments.All subjects had E₂ concentrations within the normal range over the 24hours period. No subjects had E₂ levels below or above the normal rangeat any time of the day.

Conclusions

The TBS-1 formulations (4.0% TBS-1 gel (applied t.i.d.) and 4.5% TBS-1gel (applied b.i.d. and t.i.d.)) are rapidly absorbed with meanTestosterone peak observed within 1 hour.

Overall, the Testosterone exposure (AUC_(0-t) and C_(max)) atsteady-state is comparable between all treatments.

Independently of the formulation, approximately 86%-88% of the subjectshad an average Testosterone drug concentration (C_(avg)) within thephysiological reference range (300 to 1050 ng/dL).

The Testosterone levels are within normal range for about 14 to 16 hoursa day.

TBS-1 is safe for intranasal administration at the dosages and frequencyindicated. There are no meaningful adverse events, changes in vitalsigns or changes in laboratory results when compared to baseline.

Based on these results, no clear evidence is found to indicate a betterperformance from one of the formulations.

Example 9 TBS1A Report for 4% and 8% Bulk Gel

Objective:

To follow up on IMP-Clinical batch manufacture. Main points concernprocess flow and bulk appearance on stability.

-   -   Process flow improvement    -   Viscosity of bulk Gel    -   Stability (re-crystallization)    -   Evaluation of alternate materials sources and grades    -   In Vivo results, formulation changes to impact onset of release    -   Testing of trials using Franz Cell, trial selection

List of Raw-materials identified for use in trials:

Material name Grade Spec # Source Comments Castor Oil (Crystal O) RM004ACas-Chem Castor Oil (Virgin) RM004B — Labrafil M1944CS RM002A GattfosseDMI — RM009A Croda Transcutol P — RM008A Gattfosse Plasdone K17 RM011AISP Plasdone S630 RM013A ISP Plasdone K29-32 Sample ISP Plasdone K90Sample ISP HPC Klucel HF RM014A Hercules HPC Nisso H Sample Nisso HPCNisso M Sample Nisso HPC Nisso L Sample Nisso Cab-O-Sil M-5P RM003ACabot Aerosil 200 RM003B Evonik Purified water — — Trimel Testosteronemicronized RM001A Proquina Oleic Acid Super- sample Croda refinedTestosterone Not RM Proquina micronizedEquipment Used:

In addition to the Silverson High Shear mixer, used only during themanufacture of the TBS1A IMP Clinical batches, included also a propellertype mixing unit for the trials on several pre-mix operations. The onlyapplication for the High shear action is for dispersion of the active inthe Co-Solvents.

For more uniform mixing and control of temperature, recommend a jacketedcontainer with wiping blades to remove material from inner bowl wall(especially critical for uniform bulk temperature during heating as wellas cooling cycles.

Background Info on IMP Bath Manufacture

Observation during the IMP Clinical batch manufacture included highviscosity during preparing the pre-mixture of the DMI/Transcutolco-solvent mix consisting of PVP K17/5640, Klucel HF and Testosteronemicronized. Mixture resulting in a sticky mass when added to the Castoroil using the high shear mixer set up. With the same high shear mixerset up for the addition of the Cab-O-Sil (referenced in future to SiO2)could not obtain a vortex to incorporate the material and requiredadditional manual mixing during addition stage, hence the recommendationfor propeller type mixing unit). Even though the material was viscousduring that addition stage, on further mixing the viscosity of the finalBulk Gel dropped to approximately 1,500-2,000 cps. Mixing time and speedhad to be controlled not to overshoot targeted gel temperature (nocooling system).

Outline of Trials:

The initial trials (Placebo) concentrated on changing the order ofaddition to identify impact on viscosity. Previous process included theaddition of the SiO2 at the final stage (see comments above), changed todispersion of the SiO2 into the Castor oil prior to addition of thealternate active mixture. The resulting viscosity of the Castor Oil/SiO2mixture, used various percentages, increased with the addition of asmall percentage of Arlasolve (DMI).

Next step was to duplicate these results using the active mixture(Co-solvents/PVP/HPC/active) and added that mixture to the premix ofCastor oil and SiO2. This however resulted in a low viscosity solution,indicating an impact of the active mixture on formation of a viscousgel.

Since the co-solvent mix without additional materials resulted in anincrease of viscosity, the quantities of solvent were split into 2parts, adding part of the solvent mix only to the Oil mixture andremaining solvent mix used to disperse the PVP, HPC and active. Theactive mixture with the reduced co-solvent ended up more viscose, plussimilar low viscosity when added to the castor Oil premix. Additionaltrials included the prep of active in only DMI (no PVP) and obtainedgood viscosity. HPC was prepared separately in the Transcutol P,creating problems of stringing when added to the mixture (similar to IMPobservations). Addition of SiO2 at a level of 0.1-0.3% resolved theproblem.

The above process to dissolve active in the Co-solvents is sufficientand doesn't require PVP to increase solubility for the 4% formulation,however not sufficient co-solvents in the formulation to achievesolubility for the 8% strength. Trials on the 8% included an alternatesuccessful approach for preparing the active dispersion containing PVPby including SiO2 into that mixture. As demonstrated on evaluationtrials evaluating impact of SiO2 added to the DMI as well as TranscutolP, resulted in good viscosity forming with DMI, however not withTranscutol. Active dispersion therefore id prepared by dissolving thePVP in DMI only, followed by addition of the active at 55 C (50-60 C)and portion of available SiO2.

Please note that this process was only developed during the trial workon the 8%, hence it can be scaled down to the 4% strength if PVPindicate additional functionality (Franz Cell test).

Comments related to addition of purified water (noted in Table xxx)indicate increase in viscosity with trials containing HPC, no viscosityincrease in trials using only PVP. These trials were only included forinformation to study water uptake and impact on viscosity afterapplication into the nasal cavity.

Critical step during HPC set up is to provide at least 24 hours ofsolvating to obtain a clear solution.

As outlined in the trial objectives, formulation ratios were implementedusing also alternate grades and sources of materials and are identifiedin the formulation table. To identify the impact of the process change(such as reaction of viscosity increase adding the co-solvents),performed trials to study impact if related to DMI or Transcutol P.Trials were initiated to disperse SiO2 (at the same ratio as used forCastor Oil mixture) in DMI only as well as in Transcutol P only. TheMixture with the DMI resulted in a viscous mixture while Transcutol Pmixture was very fluid.

Similar trials were initiated to use the co-solvents individually tostudy solubility of the Polymers as well as active for potentialreduction in Transcutol P. No noticeable difference in solubility usingthe mixture or individual solvents at the 4% strength. However, if PVPand HPC are prepared only in DMI, observed separation of the twomaterials when stored overnight (not apparent when mixed in theco-solvent mixture). To eliminate the stickiness of the dispersion whenadding the active/polymer mixture, removed the HPC from the formulationand using PVP only (individual grades K17-K29/32-K90, no mixtures). Thisresulted in various degrees of viscosity related to the grade used.

Material also included the use of Labrafil M 1944 CS and are outlined inbatch description and selected for testing in Franz Cell.

Comments:

The various trials are outlined below for 4% strength as well as 8%.

Trial lots of both strength have been selected for testing on the FranzCell. Selected lots are identified.

All trials will be monitored for physical evidence of re-crystallizationand change in appearance (separation), tested for change in viscosity.Viscosity values of the trials will be documented and updated

Pending Franz Cell result evaluation, optimization of formulation andprocess can be implemented. This is critical to identify since the trialoutline did not include impact on viscosity related to all processparameters (need to include analytical testing and stability data).

Observations during viscosity test using the Brookfield Viscometer ModelDV-II+, with Spindle #6, at 50 rpm for 30 seconds, did actually show anincrease in viscosity values over the test time in samples prepared withhigher viscosity grade HPC. This can be attributed to the stickiness ofthe Gel causing agglomeration to the spindle shaft and disk creating adrag (not a true viscosity value of the results reported). The bulk Gelof several trials is not thixotropic. Also tested on some trialsviscosity at 37 C.

Tested several trials using the new Haupt method with spindle 4 at 6rpm.

The various attached tables show the trial numbers for active Gels,pre-mixes and Placebos

Discussion and Considerations for Follow Up Trials with Both Strength

Even though ‘viscosity improvement’ was not the primary target toinitiate trials, it was certainly a designed effort to study the causefor low viscosity considering the high percentage of SiO2 present in theformulation. A cross check against SiO2 alternate source comparison didnot indicate major differences, nor did various ratios of Co-Solvents,limited adjustment since a certain percentage required to dissolve theTestosterone. Changes in grades of PVP indicated impact on viscositywhen used in the active dispersion, however not when added to the restof the mixture. Changes in grades of HPC (used alternate source of finematerial) showed impact on the final Gel, however the higher theMolecular weight of the HPC, impact of stickiness and stringing in thefinal Gel. Testing viscosity after several weeks did show a separationin the Gel of viscose settlement on the bottom of the container.

With indication of SiO2 retaining Testosterone, adding more to increaseviscosity was not an option, aim was to reduce the % used. especiallyfor the TBS1A 4% strength which indicated a much higher percentage of Tretained compared to the 8% TBS1A. Target was to at least obtain thesame ratio of SiO2 to T of the 8% strength for the 4% strength (henceaimed for scale down to 3%). With the trials completed and showingimpact on viscosity related to process and formulation changes, areduction in SiO2 for the definitely possible for the 4% strength thatwould also include the use of PVP in the formulation by taking advantageof the process change on the 8% strength. The above is only based onviscosity; however impact on the changes in formulation to slow downinitial absorption rate in vivo can only be evaluated from the dataobtained on the trials used for the analytical test using the FranzCell. These results will be reviewed and evaluated with potentialrecommendations for further trials to either duplicate earlier trials orbased on DOE.

The attached Tables for viscosity show the date of manufacture andlatest test results (to help with trial selection on Franz Cell). In theComment column original data will be reference or referenced in theTrial process description.

Further alternate material source evaluation is recommended once aprimary formulation and process for each strength has been establishedfor direct comparison.

Formulation/Composition of TBS1A—4%

TABLE 1A (See the formulations in the Examples above and includingExample 10) SiO2 % Trial Active Castor oil Labrafil PVP grade DMITranscutolP HPC Nisso C = Cabosil number % % % % % % % A = Aerosil200RD11037 4 52  000000 K17 = 3   25    10  0000000 C = 4   S630 = 2   RD11038 4 57  000000 K17 = 3   20    10  0000000 C = 4   S630 = 2   RD11039 4 29    29 K17 = 3   20    10  0000000 C = 3   S630 = 2   RD11040 4 57 0000000  0000000 25    10 00000000 C = 4   6 + 4 RD11041 453 0000000 K17 = 3   25    10  0000000 C = 3   S630 = 2    6 + 4 RD110424 29    29 00000000 25    10  000000 C = 3   6 + 4 (split) RD11050 466.7  000000 K17 = 3   24  0000000 N − H = 0.3  A = 2   20 + 4 RD11050A4 66.7  000000 K17 = 3   24  0000000 N − H = 0.3  1% additional 20 + 4to final 11050 RD11051 4 66.7  000000 K30 = 3   24  0000000 N − M =0.3   A = 2   20 + 4 RD11051A 4 66.7  000000 K30 = 3   24  0000000 N − M= 0.3   1% additional 20 + 4 to final 11051 RD11053 4 61.7  000000 K17 =3   22     6 N − H = 0.3  A = 3   16 + 6 4 + 2 RD11054 4 61.4  000000K30 = 3   23     5 N − M = 0.6   A = 3   16 + 7 4 + 1 RD11055 4 62.0 000000 K90 = 3   23     5  0000000 C = 3   16 + 7 4 + 1 RD11056 4 62.0 000000 K90 = 3   28   00000  0000000 C = 3   20 + 8 RD11059 4 75.0 000000 K30 = 2.5 14     2  0000000 C = 2.5 10 + 4 RD11060 4 71.5 000000 K30 = 2.0 18     1 00000000 C = 3.5  9 + 9 RD11061 4 71.0    2K17 = 2   16     2  0000000 C = 3   RD11062 4 62.35 0000000 K17 = 1.5 22    6 N − H = 0.15 A = 3   K30 = 1.0  6 + 16 2 + 4 RD11063 4 70.500000oo K17 = 1.5 18 00000000 N − H = 0.2  A = 4   K30 = 1.5  6 + 12RD11064 Transfer Add 0.3% Increase Formula from H2O in includes RD11062viscosity HPC RD11065 Transfer Add 0.3% Increase Formula from H2O inincludes RD11063 viscosity HPC RD11066 Transfer Add 0.3% No N0 HPC fromH2O increase RD11041 in viscosity RD11070 Transfer Add 0.3% No N0 HPCfrom H2O increase RD11037 in viscosity RD11071 Transfer Add 0.3% No N0HPC from H2O increase RD11042 in viscosity RD11072 Transfer Add 0.3% NoN0 HPC from H2O increase RD11040 in viscosity RD11073 4 70.5  000000 0000000 16     6 (3) N − M = 0.5  A = 3    10 + 6 (3) (0.25) RD11074Transfer Add 0.3% Transfer Add 0.3% H2O from H2O from RD11073 RD11040RD11075 4 68.0  000000 K30 = 1.0 16  0000000 See HPC A = 3   (base)  6 +10 pre-mixes RD11076 Base of — — — — — Addition — RD11075 RD11067RD11077 Base of — — — — — Addition — RD11075 RD11068 RD11078 Base of — —— — — Addition — RD11075 RD11069 RD11079 Transfer Add 0.3% — — — —Formula — from H2O includes RD11076 HPC RD11080 Transfer Add 0.3% — — —— Formula — from H2O includes RD11077 HPC RD11081 Transfer Add 0.3% — —— — Formula — from H2O includes RD11078 HPC RD11082 4 81.0  000000 0000000 10 See See 00000000 See RD11073 (3 RD11073 RD11073 (3 (0.25)RD11085 4 70.7  000000  0000000 16     6 N − L = 0.2  A = 2.8 10 + 6 N −M = 0.3   RD11086 4 70.7  000000  0000000 16     6 N − L = 0.2  A = 2.8Add 0.3% 10 + 6 N − M = 0.3   H2OLot #RD11037

Process duplication of IMP batch (4%) without HPC. K17 and S630dissolved in DMI/Transcutol mixture followed by addition of the active.Clear solution. Castor oil preheated and added the above active mixture.Clear solution observed. Followed with the addition of the Cabosil withlow shear. Viscosity at time of manufacture 500 cps, followed with testafter 48 hours resulted in 620 cps.

Lower viscosity primarily due to missing HPC (note that IMP 4% hadapprox 1,500 cps)

Lot #RD11038

Change in order of addition using the same formulation with a reductionof DMI/Transcutol and adjusted with castor oil. Cabosil was mixed intothe Castor oil obtaining a clear viscous solution. The active mixturewas prepared as per RD11037. Viscosity of the Castor oil/Cabosil mixturechanged to 1180 cps (expected higher viscosity based on addition of CoSolvents during the Placebo trials). Potential impact of PVP and activeto solvent mixture.

Lot #RD11039

Duplicated performance based on Placebo mixture also containing Labrafilin castor oil plus Cabosil (for IP). Same reaction of reduced viscositywhen adding the active mixture.

Lot #RD11040

Duplicated Placebo process adding to the Castor oil/Cabosil mixture aportion of the DMI/Transcutol P co-solvent mixture. Viscosity of the oilmixture increased. Prepared the active mixture with the remainingco-solvents without the PVP and added to the oil mixture. Finalviscosity of the bulk Gel was 10,400 cps. Potential for F/C.

Lot #RD11041

Process was repeated as per RD11040 including the PVP K17 and S630 withthe active mixture and viscosity was reduced to 500 cps (increased to1,500 cps after 3 weeks). Clear indication of PVP impact on loweringviscosity using K17 and S630.

Lot #RD11042

Repeat of trial with Castor oil/Labrafil addition as per RD11037, andreduced Cabosil, with active co solvent mixture but no PVP. Viscosity of1,750 cps

The following trials were designed to identify impact of changing tohigher PVP grades as well as alternate source of HPC (2 grades). Premixture were made as outlined in table 3 concentrating on mixtureswithout Labrafil, using Castor oil native and Aerosil 200.

Lot #RD11050

Dispersion (pre-mix I) of Castor Oil and Aerosil 200 was prepared andviscosity increased by adding part of the DMI (4%). The preparation ofthe active mixture use the pre-mix of RD11047A (PVP K17-3%) in DMI only,added 0.3% of HPC Nisso H followed by addition of active. Active mixturewas added to the Pre-mix I

Lot #RD11050A

Same basic formulation as RD11050 with change of adding to a portionadditional 1% of Aerosil 200

Lot #RD11051

Dispersion (pre-mix I) of Castor Oil and Aerosil 200 was prepared andviscosity increased by adding part of the DMI (4%). The preparation ofthe active mixture use the pre-mix of RD11047B (PVP K30-3%) in DMI only,added 0.3% of HPC Nisso M followed by addition of active. Active mixturewas added to the Pre-mix I

Lot #RD11051A

Same basic formulation as RD11051 with change of adding to a portionadditional 1% of Aerosil 200

Lot #RD11053

Dispersion (pre-mix I) of Castor Oil and Aerosil 200 was prepared andviscosity increased by adding part of the DMI and Transcutol P. Thepreparation of the active mixture use the pre-mix of RD11048A (PVPK17-3%), added 0.3% of HPC Nisso H followed by addition of active.Active mixture was added to the Pre-mix I

Lot #RD11054

Dispersion (pre-mix I) of Castor Oil and Aerosil 200 was prepared andviscosity increased by adding part of the DMI and Transcutol P. Thepreparation of the active mixture use the pre-mix of RD11048B (PVPK30-3%), added 0.3% of HPC Nisso H followed by addition of active.Active mixture was added to the Pre-mix I

Lot #RD11055

Dispersion (pre-mix I) of Castor Oil and Aerosil 200 was prepared andviscosity increased by adding part of the DMI and Transcutol P. Thepreparation of the active mixture use the pre-mix of RD11048C (PVPK90-3%). No HPC added. Active mixture was added to the Pre-mix I

Lot #RD11056

Dispersion (pre-mix I) of Castor Oil and Aerosil 200 was prepared andviscosity increased by adding part of the DMI. The preparation of theactive mixture use the pre-mix of RD11047C (PVP K90-3%). No HPC addedActive mixture was added to the Pre-mix I

Lot #RD11059

Prepared mixture of Castor Oil and Cabosil (2.5%). Active was dissolvedin DMI and Transcutol P. Resulted in milky appearance. Adding that mixto the Castor Oil pre-mix, mixture did not clear up. Prepared the PVP(K30) solution with DMI, added to the mix, no change in appearancehowever reduced viscosity.

Note, no change in evaluation adding a mixture of 0.1% HPC toappearance, slight increase in viscosity. Trial not reported under triala lot number.

Lot #RD11060

Prepared the Castor Oil adding 3.5% Cabosil, followed by addition of amixture of DMI/Transcutol P for thickening. The active dispersion wasprepared in a PVP (K30) with DMI as co-solvent. (no HPC)

Lot #RD11061

Prepared the Castor Oil adding 3% Cabosil, followed by addition ofLabrafil (2%) for thickening. The active dispersion was prepared in aDMI mixture containing PVP K17 (2%). Mix resulted in low viscosity,however could be considered for F/C test.

Lot #RD11062

Castor Oil native mixed with Aerosil 200 (3%) and added a mixture ofDMI/Transcutol P (6+2) for thickening. A PVP mixture of K17 and K30 wasdissolved in DMI/Transcutol P and followed with HPC H and solvate for 4days. Mixture was reheated prior to addition of active. Castor Oilpremix was heated prior to adding the active dispersion. Recommended forF/C

Lot #RD11063

Castor Oil native mixed with Aerosil 200 (4%) and added the DMI (6%)resulting in a high viscose mix. A mixture of PVP K17 and L29/32 wasdissolved in DMI, plus HPC Nisso H (0.2). On overnight setup, noticed aseparation, required re-mixing. Active was added to the high viscosityCastor Oil premix. To be followed up with modification to composition

Potential for F/C or to use RD11065

Lot #RD11064

Addition of 0.3% to portion of lot RD11062

Lot #RD11065

Addition of 0.3% to portion of lot RD11063

Lot #RD11066

Addition of 0.3% to portion of lot RD11041

Lot #RD11070

Addition of 0.3% to portion of lot RD11037

Lot #RD11071

Addition of 0.3% to portion of lot RD11042

Lot #RD11072

Addition of 0.3% to portion of lot RD11040

Lot #RD11073

Prepared Castor Oil/Aerosil 200 pre-mixture. Dissolve in DMI (6%)without PVP, the Testosterone and add to the Castor oil pre-mix.Obtained a viscosity of 6,300 cps. In a mixture of Transcutol P and DMIdisperse the HPC M (only used 0.25% of prep) and add to main mix.Proposed for F/C

Lot #RD11074

Addition of 0.3% to portion of lot RD11072

Lot #RD11075

Prepared a stock mixture to complete 3×500 g trials consisting ofCastor-Oil (68%) Aerosil 200 (3%) DMI (6%). To this mix was added PVPK29-32 (1%) in DMI (10) and active. Bulk split into 3 parts to becompleted for 3 trials containing different mixtures and grades of HPCNisso in Transcutol (ref lots RD11067/68/69)

Lot #RD11076

Used bulk from RD11075 and added HPC mix RD11067 (Transcutol P withNisso H (0.15%)

Lot #RD11077

Used bulk from RD11075 and added HPC mix RD11068 (Transcutol P withNisso H (0.2%)

Lot #RD11078

Used bulk from RD11075 and added HPC mix RD11069 (Transcutol P withNisso H (0.1) and M (0.1)

Lot #RD11079

Addition of 0.3% to portion of lot RD11076

Lot #RD11080

Addition of 0.3% to portion of lot RD11077

Lot #RD11081

Addition of 0.3% to portion of lot RD11078

Lot #RD11082

Trial attempt to prepare a batch without the use of SiO2 failed

Lot #RD11085

Prepared Castor-Oil pre-mix adding 2.5% Aerosil 200 followed with a mixof DMI (10) and Testosterone. Obtained viscosity of 3,100 cps. Followedwith the addition of HPC Nisso L (0.2%) and Nisso M (0.3%) mixed in DMIand Transcutol plus 0.3% Aerosil 200 to reduce stickiness. Material wasadded without any stringing to the main mixture and obtained a viscosityof 4,800 cps at day of manufacture and 4,900 cps 3 weeks later. Proposedfor F/C

Lot #RD11086

Addition of 0.3% to portion of lot RD11085

TABLE 2 TBS1A 4% strength Viscosity values using spindle 6, 20 rpm,Repeat test ref to Franz Cell: F/C Trial Manuf Lot number date Test dateand values Comments RD11037 Jul. 15, 2011 Oct. 4, 2011 Clear solution,previous results in July 620 cps   940 cps and follow up test Sep. 15,2011 was 900 cps RD11038 Jul. 15, 2011 Oct. 4, 2011 Clear solution,original test 1,180 cps, follow up 1,800 cps Sep. 15, 2011 1,660 cpsRD11039 Jul. 20, 2011 Oct. 4, 2011 Clear solution, previous results inJuly 980 cps 1,380 cps and follow up test Sep. 15, 2011 was 1,300 cpsRD11040 Jul. 20, 2011 Oct. 4, 2011 Clear Gel, previous results in July10,400 cps 11,040 cps  and follow up test Sep. 15, 2011 was 10,140 cpsRD11041 Jul. 21, 2011 Oct. 4, 2011 Clear solution, previous results inJuly 500 cps 1,420 cps and follow up test Sep. 15, 2011 was 1,500 cpsRD11042 Jul. 21, 2011 Oct. 4, 2011 Clear solution, test Sep. 15, 2011was 1,720 cps 1,430 cps RD11050 Aug. 9, 2011 Oct. 4, 2011 Originalcomment sticky mixture, Sep. 15, 2011 Test not valid results 2,460 Donot use trial lot for F/C Poor mixture, HPC settled to bottom as a slugRD11050A Aug. 9, 2011 Oct. 4, 2011 Original comment sticky mixture,results Test not valid Sep. 15, 2011 3,000 cps (increased during testfrom 2,400) Do not use trial lot for F/C Poor mixture, HPC settled tobottom as a slug RD11051 Aug. 9, 2011 Oct. 4, 2011 Clear, results Sep.15, 2011 1,940 cps  2,100 cps▴ Note: viscosity values increase during 30sec test RD11051A Aug. 9, 2011 Oct. 4, 2011 Clear, results Sep. 15, 20112,560 cps  2,540 cps▴ Note: viscosity values increase during 30 sec testRD11053 Aug. 10, 2011 Oct. 4, 2011 Clear but sticky with air bubbles,results  4,500 cps▴ Sep. 15, 2011 4,060 cps Note: viscosity valuesincrease during 30 sec test RD11054 Aug. 10, 2011 Oct. 4, 2011 Sep. 15,2011 test HPC globules, 15,000 cps 14,000 cps▴ Do not use trial lot forF/C, Note: viscosity values increase during 30 sec test Build up of HPCon spindle RD11055 Aug. 10, 2011 Oct. 4, 2011 Sep. 15, 2011, EEEEEEEEEEEE Do not use trial lot for F/C Note, error message indicates above20,000 tester limit at that setting RD11056 Aug. 10, 2011 Oct. 4, 2011Sep. 15, 2011, EEEEEE EEEEEE Do not use trial lot for F/C Note, errormessage indicates above 20,000 tester limit at that setting RD11059 Aug.22, 2011 Oct. 4, 2011 Do not use trial lot for F/C Test not validSeparation of HPC (?)Build up of HPC on spindle RD11060 Aug. 23, 2011Oct. 5, 2011 Uniform texture 3,540 cps RD11061 Aug. 23, 2011 Oct. 5,2011 Uniform texture   960 cps RD11062 Aug. 24, 2011 Oct. 5, 2011Original viscosity 2,400 cps 3,200 cps RD11063 Aug. 24, 2011 Oct. 5,2011 Original viscosity 1,600 cps 3,460 cps RD11064 Aug. 31, 2011 Oct.5, 2011 Original viscosity 5,800 cps 6,440 cps Clear, thick, RD11065Aug. 31, 2011 Oct. 5, 2011 Added .3% H2O to RD11063 Sep. 31, 2011 12,500cps  resulted in 9,100 cps Air bubbles RD11066 Aug. 31, 2011 Oct. 5,2011 Added .3% H2O to RD11041 Sep. 31, 2011 2,600 cps resulted in 1,500cps Clear, thick RD11070 Aug. 31, 2011 Oct. 5, 2011 Added .3% H2O toRD110370 Sep. 31, 2011 1,540 cps resulted in 720 cps Liquid and clearRD11071 Aug. 31, 2011 Oct. 5, 2011 Added .3% H2O to RD11042 1,820 cpsSep. 31, 2011 resulted in 1,760 cps Liquid and clear RD11072 Aug. 31,2011 Oct. 5, 2011 Added .3% H2O to RD11040 resulted in 7,920 7,920 cpscps Clear and thick, no change in viscosity RD11073 Sep. 7, 2011 Oct. 5,2011 Started off in Sept with viscosity of 5,500 cps 9,980 cps RD11074Sep. 7, 2011 Oct. 5, 2011 Added .3% H2O to RD11073 increases viscosity10,100 cps  to 7,200 cps. RD11076 Sep. 6, 2011 Oct. 5, 2011 Clear,however noticed separation in bulk 1,700 cps RD11077 Sep. 6, 2011 Oct.5, 2011 Clear 1,600 cps RD11078 Sep. 6, 2011 Oct. 5, 2011 Clear andfluid 2,700 cps RD11079 Sep. 6, 2011 Oct. 5, 2011 Added 0.3% H2O toRD11076 3,500 cps Clear, fluid RD11080 Sep. 6, 2011 Oct. 5, 2011 Added0.3% H2O to RD11077 3,900 cps Clear, fluid RD11081 Sep. 6, 2011 Oct. 5,2011 Added 0.3% H2O to RD11078 2,600 cps Clear, fluid RD11085 Sep. 14,2011 Oct. 5, 2011 Original test 4,800 cps 4,900 cps Thick and clearRD11086 Sep. 20, 2011 Oct. 5, 2011 Addition of 0.3% H2O to RD11085 =5,200 cps 5,180 cps original Thick gel and clearTBS1A 8% Formulation/Composition

TABLE 3 Active SiO2 % Trial micronized Castor oil Labrafil PVP grade DMITransbutolP HPC Nisso C = Cabosil number % % % % % % % A = Aerosil200RD11087 8 55.9 0000000 0000000 27  6  N − L = 0.2 A = 2.6 20 + 7 N − M =0.3 RD11088 8 same 0000000 0000000 same same same Same plus (0.3% H2O)RD11089 8 46.5 0000000 K17 = 3 25 10 N − M = 0.5 C = 5   S630 = 2 RD11089A 8 same 0000000 same same same same Same plus (0.3% H2O) RD110908 39.0 0000000   K17 = 5.0 32 12  N − H = 0.3 C = 3.5 N − M = 0.2RD11100 8 same 0000000 same same same same Added C = 2% for total of 5.5RD11101 8 46.1 0000000   K17 =5.0 25 10  N − L = 0.4 C = 5.1 N − M = 0.4RD11102 8 46.1 0000000   K17 = 5.0 25 10  N − L = 0.4 C = 5.1 plus N − M= 0.4 Addition of 1% for total of 6.1 RD11103 8 46.1 0000000   K17 =5.025 10  N − L = 0.4 C = 5.1 plus N − M = 0.4 addition of 0.3% waterRD11104 8 42.2 4.0   K17 = 5.0 25 10  N − L = 0.4 A = 5.0 N − M = 0.4RD11105 8 same same same same same same A = 5.0 addition of 0.5% total5.5%Process Outline for Active Trials:Lot #RD11087

Trial was initiated without PVP to identify impact on T solubility. Theactive dispersion in % DMI used did not provide a clear solution and didnot clear up when adding to the Castor Oil/SiO2 mix. Even theco-solvents present in the HPC mixture did not provide a clear bulk Gel.To the HPV mixture 0.1% SiO2 was added to reduce stringing andstickiness.

Viscosity at 4,400

This trial however will be selected for the Franz Cell test to identifydiffusion rate eliminating PVP.

Lot #RD11088

0.3% water was added to a portion of Lot RD11087 to identify impact onviscosity. As observed on 4% trials, increase in viscosity is notevident on the bulk mixed with SiO2 in the HPC. This trial notconsidered for F/C.

Lot #RD11089

This trial used the same quantitative formulation as the IMP Clinical8%, however using an alternate source of HPC (original HPC source KlucelHF). Also made minor process changes, dissolved PVP in DMI only andadded active. HPC was prepared in Transcutol and added to main bulkseparately.

Obtained a clear solution when adding the active co-solvent mixture intothe Castor-oil and no significant stringing with the addition of the HPCafter addition of SiO2.

Viscosity of Gel on day of manufacture was 1,800 cps, when retestedafter 24 hours, 3,700 and after 48 hours up to 4,300. The re-test onOctober 3 (see table) recorded 4,500 cps.

This trial was selected for F/C test

Lot #RD11089A

0.3% water was added to a portion of Lot RD11089 to identify impact onviscosity.

Viscosity change over time similar to above trial, day of manufacture2,700 cps, when retested after 24 hours, 3,920 and after 48 hours up to4,600. The re-test on October 3 (see table) recorded 5,040 cps.

Selected for study on impact of water

Lot #RD11090

Used higher percentage of DMI and Transcutol to be split for variouspre-mixes, similar with SiO2 to be added HPC. Made a pre-mix of Castoroil and SiO2, however due to the lower ratio between the 2 excipients,the mixture became quite thick and further thickened up when adding partof the DMI.

Did finish off the trial, ended up at low viscosity, day of manufacture900 cps, test October 03-1,260 cps. Lower level of SiO2 was consideredfor study impact, however considering the processing issue (see RD11100)

not suitable for F/C test

Lot #RD11100

Using a portion of above trial RD11090, added an additional 2% SiO2 (fortotal of 5.5%) to study impact on Viscosity. Increased to 1,900 cps onday of manufacture and retest October 03 (see table) resulted in a valueof 3.060

Lot #RD11101

To potentially reduce the impact of PVP, required to dissolve theactive, during the addition to the Castor oil/SiO2 mixture, added 2% ofSiO2 to the DMI-PVP-Testosterone mix, obtaining a viscous mix. Afteraddition of that mixture to a dispersion of Castor oil containing 1%SiO2, maintained a viscous mixture at the temperature of 50% (wouldthicken up further on cooling). Further increase in viscosity with theaddition of the HPC mix and final amount of SiO2.

Viscosity after cooling Gel to 21 C was 3,800 cps. (note that re-testingover time will be required, batch manufactured October 03)

This trial selected for F/C

Lot #RD11102

With the target for a 5,000 cps viscosity for the TBS1A project, theabove RD11101 was so far the best candidate to evaluate impact offurther addition of SiO2, hence to a portion of that lot additional 1%SiO2 was added. The rational for 6% was to obtain the same ratio ofactive to SiO2 as the targeted level of 3% SiO2 for the 4% strength.

Viscosity increase to 8,000 cps, this lot was selected for F/C study toidentify impact of viscosity on rate of diffusion compared to RD11101 ofsame composition with exception of 1% addition in SiO2, may need toconsider on assay obtained.

Lot #RD11103

Addition of water for impact on viscosity, not considered for follow uptesting (see viscosity table for results, increase to RD11101 from 3,800to 4,500 cps)

Lot #RD11104

Included this trial to evaluate addition of Labrafil. Labrafil was addedto the Castor Oil mixed with SiO2 at 1%. As observed previously,addition of Labrafil to the Castor oil containing SiO2 increasesviscosity. All other mixture prepared and added as per trial RD11101,with addition of 2% SiO2 to complete mixture. This mixture contains alarger percentage of air bubbles, common on formulations containingLabrafil. Viscosity obtained of 3,300 cps, will be followed up andtested at various time points.

Selected for F/C testing.

Lot #RD11105

Added to RD11104 an additional 0.5% SiO2 (% adjusted to avoid highincrease observed on RD11102)

Increase from 3,300 to 4,100 cps

Not selected for F/C test

Note: Placebo trials are drawn up to identify impact on viscosity usingthe 2 different sources for Castor Oil and SiO2. These trials will alsoanswer potential questions related to TBS1 and TBS2.

TABLE 4 TBS1A 8% strength Viscosity values using spindle #6, 20 rpm,Franz Cell = F/C Trial Manuf Lot number date Test date and valuesComments RD11087 Sep. 20, 2011 Oct. 3, 2011 No PVP, solution not clear,2.6% SiO2 4,400 cps Selected for Franz Cell RD11088 Sep. 20, 2011 Oct.3, 2011 Added 0.3% H2Oto RD11087 4,040 cps RD11089 Sep. 25, 2011 Oct. 3,2011 Based on original IMP, change in HPC 4,500 cps source and minorprocess step changes Selected for Franz Cell RD11089A Sep. 25, 2011 Oct.3, 2011 As RD11089 plus 0.3% H2O 5,040 cps Selected for Franz CellRD11090 Sep. 26, 2011 Oct. 3, 2011 3.5% SiO2 1,260 cps Potential for F/CRD11091 Sep. 26, 2011 Oct. 3, 2011 Added 0.3% H2O to RD11090 RD11100Sep. 26, 2011 Oct. 3, 2011 Added to RD11090 to reach 5% SiO2 3,060 cpscontent RD11101 Oct. 3, 2011 Oct. 4, 2011 5% SiO2 3,800 cps Selected forFranz Cell RD11102 Oct. 4, 2011 Oct. 4, 2011 6% SiO2 8,000 cps Selectedfor Franz Cell RD11103 Oct. 4, 2011 Oct. 4, 2011 0.3% with 5% SiO2 4,500cps RD11104 Oct. 4, 2011 Oct. 5, 2011 Includes 4% Labrafil, same compfor 3,300 cps polymers as RD11101 (air-bubbles) Selected or Franz CellRD11105 Oct. 5, 2011 Oct. 5, 2011 Added additional 0.5% of SiO2 4,100cps to RD11104Pre-Mix RD Trials (Used for Addition in Active Trials)

TABLE 5 Trial #/ observation test Evaluation CompositionResults/comments Used in RD trial # EV001A (pg 41) Dissolving HPCDMI-100 g Low viscosity grade Not transferred for Nisso grade MTranscutol P 50 g Stored for hydration use to RD trials Nisso HPC M-2.5g 72 hrs Suitable viscosity for further additions EV001B (pg 41)Dissolving HPC DMI-100 g high viscosity grade Not transferred for Nissograde H Transcutol P 50 g Stored for hydration use to RD trials NissoHPC H-2.5 g 72 hrs Viscosity too high EV002A (pg 41) Dispersing Cabosilin DMI-125 g Obtained clear and Not transferred for DMI (purpose toCabosil 10 g viscous dispersion use to RD trials study impact on Ratiorelated to viscosity in final Gel) Castor oil/Cabosil EV002B (pg 41)Dispersing Cabosil in Transcutol P 250 g Obtained no Not transferred forTranscutol P Cabosil 20 g increase viscosity, use to RD trials (purposeto study Ratio related to Solution milky in impact on viscosity Castoroil/Cabosil appearance in final Gel) RD11047 A Addition of PVP K17DMI-100 g Suitable for Used in RD trial for in DMI only. PVP K17 15 gadditional mixing addition of HPC-H Ratio represents 3% with HPC H andand active (see of PVP based on active. Note: used RD1150 and final BulkGel higher viscosity HPC RD1150A) formula grade with lower viscosity PVPgrade RD11047B Addition of PVP DMI-100 g Suitable for Used in RD trialfor K29/32 in DMI only. PVP K29/32 15 g additional mixing addition ofHPC-M Ratio represents 3% with HPC M and and active (see of PVP based onactive. Note: used RD1151 and final Bulk Gel lower viscosity HPCRD1151A) formula grade with higher viscosity PVP grade RD11047C Additionof PVP K90 DMI-100 g Not suitable to add Used in RD trial in DMI only.PVP K90 15 g any grade HPC, without HPC Ratio represents 3% howeversuitable to addition RD11056 of PVP based on add the active final BulkGel portion. formula RD11048 A Addition of PVP K17 DMI-80 g Suitable forUsed in RD trial for in DMI and Transcutol P 20 g additional mixingaddition of HPC-H Transcutol P PVP K17 15 g with HPC H and and active(see Ratio represents 3% active. Note: used RD11053 of PVP based onhigher viscosity HPC final Bulk Gel grade with lower formula viscosityPVP grade RD11048B Addition of PVP DMI-80 g Suitable for Used in RDtrial for K29/32 in DMI and Transcutol P 20 g additional mixing additionof HPC-M Transcutol P. PVP K29/32 15 g with HPC M and and active (seeRatio represents 3% active. Note: used RD11054 of PVP based on lowerviscosity HPC final Bulk Gel grade with higher formula viscosity PVPgrade RD11048C Addition of PVP K90 DMI-100 g Not suitable to add Used inRD trial in DMI and PVP K90 15 g any grade HPC, without HPC Transcutol PRatio represents 3% however suitable to addition RD11055 of PVP based onadd the active final Bulk Gel portion. formula RD11067 Prep of HPC in TP= 40 g Used in RD11076 Transcutol P only N—H = 0.75 g RD11068 Prep ofHPC in TP = 40 g Used in RD11077 Transcutol P only N—H = 1.0 g RD11069Prep of HPC in TP = 40 g Used in RD11078 Transcutol P only N—H = 0.5 gN—M = 0.5 g RD11075 Prep of base Castor oil/ solution used Aerosil200/RD11076/RD11077/ DMI/ RD11078 PVP K30 Details in Table 2 TestosteronePlacebo TBS1A Trials

TABLE 6 Trial lot # Evaluation Composition Results/comments RD11032Evaluate change in Labrafil M 1944 CS-500 g Viscosity 10,460 cpsviscosity using Labrafil Cab-O-Sil - - - 40 g versus Castor Oil Cr 0RD11033 Evaluate change Castor Oil - - - 500 g Viscosity 14 460 cpsviscosity adding Cabosil Cab-O-Sil - - - 40 g first in Castor Oil Cr 0Note: ratio used in IMP RD11034 Impact on adding DMI and RD11032-270 gViscosity reduced to 8,740 Transcutol to mixture DMI-125 g RD11032Transcutol P 50 g RD11035 Impact on adding DMI and Impact on adding DMIand Viscosity reduced to 3,600 Transcutol to mixture Transcutol tomixture RD11033 RD11032 RD11036A Mixture of Castor Oil and Castor oil .. . 125 g High viscosity out of range Labrafil, adding Cabosil Labrafil. . . 125 g followed by Cabosil . . . 20 g DMI/Transcutol P DMI . . .125 g Transcutol P 50 g RD11036B Mixture of Castor Oil and Castor oil 0. . . 125 g Viscosity 7,680 cps Labrafil followed by Labrafil . . . 125g DMI/Transcutol P, add Cabosil . . . 20 g Cabosil last DMI . . . 125 gTranscutol P 50 g RD11043 Castor oil and Cab0sil, Castor oil 0 . . . 285g followed by mixture of Cabosil . . . 20 g DMI/Transcutol P and DMI . .. 100 g HPC H Transcutol P 50 g HPC H . . . 2.5 g RD11043 Castor oil andCab0sil, Castor oil 0 . . . 285 g followed by mixture of Cabosil . . .20 g DMI/Transcutol P and DMI . . . 100 g HPC M and PVP K17 Transcutol P50 g HPC M . . . 2.5 g PVP K15 . . . 15 g RD11057P TBS-2 Placebo for — —Analytical Lab Method RD11058P Castor oil an Cabosil A to D represents %RD11058P = 2740 cps A-B-C-D-E-F Mix followed by addition Labrafil of2-4% with Part A 2% = 11,400 of Labrafil change in viscosity Part B 3% =14,000 E impact of adding Oleic Part C 3.5% = 14,440 acid Part D 4% =14,900 F impact of adding DMI to Part E with Oleic = 1,520 RD11058-APart F-10% DMI to part A = 13,500 cps (incr. from 11,400) RD11083PPurpose of trial to HPC mix prep of Viscosity of base prior to decreasestringing and DMI/TranscutolP solvents addition of HPC mixturestickiness of HPC mixture plus Nisso HPC L and M was 5,300 cps, afterwhen adding to base mix Solvated for 48 hours addition of HPC mixture ofcastor oil/Aerosil and followed by addition of (no stringing DMI SiO2RD11084P Used part of RD1108P to add 0.3% H2O to evaluate impact onviscosity

Example 10 Franz Cell Studies—Testosterone Rates of Diffusion

Generally speaking, soak the membrane for 30 minutes in the diffusionsolution. After put the membrane on the Franz Cell. Put the ring and thedonor chamber on the membrane and clamp it. Add approx. one gram of gel(TBS 1 A 4% or 8%). Check the level of diffusion solution in FranzCells. It's supposed to be on the mark. Put “parafilm” on the samplingport to avoid evaporation. Withdraw 0.3 mL of sample at 60, 120, 180,240, 300 and 360 minutes using syringe. Add diffusion solution to makeup to the mark of Franz Cells. Each sample should be collected ininsert.

A typical Fanz cell used in accordance with this Example 9 and theinvention is depicted in FIG. 12 . The materials include:

-   -   Diffusion solution: Ethanol/Water 50:50    -   Membrane: Millipore 0.45 μm.    -   Temperature: 37°±0.5° C.    -   Stirring speed: 600 rpm.    -   Medium volume: 20 mL.    -   Surface area: 1.7671 cm²    -   Number of Franz Cells: 6.    -   Sampling time (minutes): 60, 120, 180, 240, 300 and 360.    -   Aliquot volume: 0.3 mL.    -   Insert: 0.4 mL.

The TBS1A formulations are as follows and as reported in the Examplesabove and herein. The rate of diffusion results of testosterone throughthe Franz cell membrane, normalized for each gel concentrations beingtested, measured as slope/mgT %, are reported below in the Franz CellTable.

4% TBS1A Trial formulations used in Franz Cell Raw Materials/grade %Process comments Trial Lot # RD11063 Batch size 500 g 24 hr Franz CellTestosterone micronized 4.0 12% DMI to disperse PVP and active CastorOil (V-O) 70.8 4% SiO2 in Castor oil plus 6% of DMI Steps: PVP K17 1.5A: add all SiO2 to Castor Oil PVP K30 1.5 Followed by DMI portion PVPK90 0.0 B: to the DMI add PVP, follow Co PVP S630 0.0 With HPC and hold24 hrs DMI 18.0 C: add active Transcutol P 0.0 D: add to mix A) HPCNisso L 0.0 HPC Nisso M 0.0 Temp range NMT 60 C. HPC Nisso H 0.2Homogenize active mixture SiO2 (Cabosil-Aerosil 200) 4.0 Viscosity 3,650cps Oct. 5, 2011) Trial Lot # RD11085 Batch size 500 g 24 hrs Franz CellTestosterone micronized 4.0 10% DMI used to dissolve active Castor Oil(V-O) 70.7 2.5% of SiO2 mixed into Castor Oil Steps: PVP K17 0.0 — A:Active /DMI mixture added PVP K30 0.0 — to Castor Oil/SiO2 mix PVP K900.0 — B: add SiO2 to HPC after 24 h Co PVP S630 0.0 — DMI 16.0 6% DMIused for HPC dispersion C: add HPC mixture to main Transcutol P 6.0 Usedto disperse HPC and solvate for 24 hrs bulk HPC Nisso L 0.2 0.3% of SiO2mixed into HPC mixture HPC Nisso M 0.3 Temp range NMT 60 C. HPC Nisso H0.0 Homogenize active mixture SiO2 (Cabosil-Aerosil 200) 2.8 Viscosity4,900 cps (Oct. 5, 2011) Trial Lot # RD11038 Batch size 500 g 6 hr FranzCell Testosterone micronized 4.0 Add to PVP mixture Castor Oil (V-O)57.0 All Cabosil into Castor Oil A: add to the Castor Oil/SiO2 PVP K173.0 Mix the PVP active mixture PVP K30 0.0 PVP K90 0.0 Co PVP S630 2.0DMI 20.0 All DMI and Transcutol P to disperse PVP Transcutol P 10.0 HPCNisso L 0.0 HPC Nisso M 0.0 Homogenize active mixture HPC Nisso H 0.0SiO2 (Cabosil-Aerosil 200) 4.0 Viscosity 1,800 cps Trial Lot # RD11039Batch size 500 g 6 hr Franz Cell Testosterone micronized 4.0 Castor Oil(V-O) 29.0 Mix Castor oil + Labrafil + Cabosil PVP K17 3.0 PVP K30 0.0PVP K90 0.0 Co PVP S630 2.0 PVP into DMI + Tr-P followed by active DMI20.0 Transcutol P 10.0 Labrafil 29.0 HPC Nisso M 0.0 HPC Nisso H 0.0SiO2 (Cabosil-Aerosil 200) 3.0 Viscosity 1,380 Trial Lot # RD11040 Batchsize 500 g 6 hr Franz Cell Testosterone micronized 4.0 Mix in 12% DMIand 6% Tr-P Castor Oil (V-O) 57.0 Combine Castor oil + SiO2 + 13% DMI +4% TrP PVP K17 0.0 PVP K30 0.0 PVP K90 0.0 Co PVP S630 0.0 DMI 25.0Transcutol P 10.0 HPC Nisso L 0.0 HPC Nisso M 0.0 HPC Nisso H 0.0 SiO2(Cabosil-Aerosil 200) 4.0 Viscosity 11,040 Trial Lot # RD11042 Batchsize 500 g 6 hr Franz Cell Testosterone micronized 4.0 Active dissolvein 13% DMI + 4% Tr-P Castor Oil (V-O) 29.0 Castor oil + Labrafil +SiO2 + 12% DMI + 6% Tr-P PVP K17 0.0 PVP K30 0.0 PVP K90 0.0 Co PVP S6300.0 DMI 25.0 Transcutol P 10.0 Labrafil 29.0 HPC Nisso M 0.0 HPC Nisso H0.0 SiO2 (Cabosil-Aerosil 200) 3.0 Viscosity 1,430 cps Trial Lot#RD11051 Batch size 500 g 6 hr Franz Cell Testosterone micronized 4.020% DMI + PVP + N − M + 0.2% iO2 Castor Oil (V-O) 66.7 Castor Oil + SiO21.8% + 4% DMI PVP K17 0.0 Easier addition of HPC adding PVP K30 3.0Small % of SiO2 PVP K90 0.0 Co PVP S630 0.0 DMI 24.0 Transcutol P 0.0HPC Nisso L 0.0 HPC Nisso M 0.3 HPC Nisso H 0.0 SiO2 (Cabosil-Aerosil200) 2.0 Viscosity 2,100 cps Trial Lot # RD11055 Batch size 500 g 6 hrFranz Cell Testosterone micronized 4.0 DMI 16% + Transc 4% + pvp +active Castor Oil (V-O) 62.0 Castor Oil + SiO2 3% + 7% DMI + Trans 1%PVP K17 0.0 PVP K30 0.0 PVP K90 3.0 Co PVP S630 0.0 DMI 23.0 TranscutolP 5.0 HPC Nisso L 0.0 HPC Nisso M 0.0 HPC Nisso H 0.0 SiO2(Cabosil-Aerosil 200) 3.0 Exceeded test range Trial Lot # RD11078 Batchsize 500 g 6 hr Franz Cell Testosterone micronized 4.0 Castor Oil (V-O)68.0 Castor oil + SiO2-3% + 6% DMI To be corrected to 67.8% PVP K17 0.0for repeat (base) PVP K30 1.0 DMI 10% + pvp + active Base prep RD11075PVP K90 0.0 Co PVP S630 0.0 DMI 16.0 Transcutol P 8.0 Transc P + bothHPC Prep on RD11069 HPC Nisso L 0.0 HPC Nisso M 0.1 Requires adjustmentof HPC Nisso H 0.1 Castor oil by 0.2% SiO2 (Cabosil-Aerosil 200) 3.0Viscosity 2,700 cps Trial Lot #RD11054 Batch size 500 g 6 hr Franz CellTestosterone micronized 4.0 Castor Oil (V-O) 61.4 Castor Oil + SiO2 3% +DMI 7% + Transc 1% PVP K17 0.0 PVP K30 3.0 DMI 16% + Trans 4% + pvp +HPC + active PVP K90 0.0 Co PVP S630 0.0 DMI 23.0 Transcutol P 5.0 HPCNisso L 0.0 HPC Nisso M 0.6 HPC Nisso H 0.0 SiO2 (Cabosil-Aerosil 200)3.0 Viscosity 14,000 cps Trial Lot #RD11061 Batch size 500 g 6 hr FranzCell Testosterone micronized 4.0 Castor Oil (V-O) 71.0 Castor oil +SiO2 + Labrafil PVP K17 2.0 DMI 16% + Transc 2% + PVP + active PVP K300.0 PVP K90 0.0 Co PVP S630 0.0 DMI 16.0 Transcutol P 2.0 Labrafil 2.0HPC Nisso M 0.0 HPC Nisso H 0.0 SiO2 (Cabosil-Aerosil 200) 3.0 Viscosity960 cps

TABLE 2 TBS1A 4% strength Viscosity values using spindle 6, 20 rpm,Repeat test ref to Franz Cell: F/C Trial Manuf Lot number date Test dateand values Comments RD11037 Jul. 15, 2011 Oct. 4, 2011 Clear solution,previous results in July 620 cps   940 cps and follow up test Sep. 15,2011 was 900 cps RD11038 Jul. 15, 2011 Oct. 4, 2011 Clear solution,original test 1,180 cps, follow up 1,800 cps Sep. 15, 2011 1,660 cpsRD11039 Jul. 20, 2011 Oct. 4, 2011 Clear solution, previous results inJuly 980 cps 1,380 cps and follow up test Sep. 15, 2011 was 1,300 cpsRD11040 Jul. 20, 2011 Oct. 4, 2011 Clear Gel, previous results in July10,400 cps 11,040 cps  and follow up test Sep. 15, 2011 was 10,140 cpsRD11041 Jul. 21, 2011 Oct. 4, 2011 Clear solution, previous results inJuly 500 cps 1,420 cps and follow up test Sep. 15, 2011 was 1,500 cpsRD11042 Jul. 21, 2011 Oct. 4, 2011 Clear solution, test Sep. 15, 2011was 1,720 cps 1,430 cps RD11050 Aug. 9, 2011 Oct. 4, 2011 Originalcomment sticky mixture, Sep. 15, 2011 Test not valid results 2,460 Donot use trial lot for F/C Poor mixture, HPC settled to bottom as a slugRD11050A Aug. 9, 2011 Oct. 4, 2011 Original comment sticky mixture,results Test not valid Sep. 15, 2011 3,000 cps (increased during testfrom 2,400) Do not use trial lot for F/C Poor mixture, HPC settled tobottom as a slug RD11051 Aug. 9, 2011 Oct. 4, 2011 clear, results Sep.15, 2011 1,940 cps 2,100 cps▴ Note: viscosity values increase during 30sec test RD11051A Aug. 9, 2011 Oct. 4, 2011 clear, results Sep. 15, 20112,560 cps 2,540 cps▴ Note: viscosity values increase during 30 sec testRD11053 Aug. 10, 2011 Oct. 4, 2011 Clear but sticky with air bubbles,results 4,500 cps▴ Sep. 15, 2011 4,060 cps Note: viscosity valuesincrease during 30 sec test RD11054 Aug. 10, 2011 Oct. 4, 2011 Sep. 15,2011 test HPC globules, 15,000 cps 14,000 cps▴  Do not use trial lot forF/C, Note: viscosity values increase during 30 sec test Build up of HPCon spindle RD11055 Aug. 10, 2011 Sep. 15, 2011, EEEEEE

The TBS-1A Gel In Vitro Release Rate Validation concerning Release RateStudy Summary for TBS-1A Gel 4.0% and TBS-1A Gel 4.5% are presented inExhibits A and B submitted herewith.

These summaries summarize the release rate experiment data for exemplaryTBS-1A Gels. There are four Nasobol Gels (0.15%, 0.6%, 4.0% and 4.5%)for the method validation. The purpose of the Day1 and Day2 test are todetermine the specificity and intraday/interday precision of the slope(release rate), Day3 and Day4 are to evaluate the slope sensitivity tothe sample strength variation.

See Exhibit A (4.0%) and Exhibit B (4.5%) submitted herewith, both ofwhich are incorporated herein by reference in their entireties.

Example 11 In Vitro Release Rate (Ivrt) Comparison Testing

IVRT experimental approach is used for comparison of products insemi-solid dosage form

through evaluation of the drug release. In order to have faircomparison, products to be compared should be of comparable age andtheir release rates should be determined on the same day, under the sameconditions. To ensure an unbiased comparison, sample position within thebank of Franz cells are randomized. The test (T) product and reference(R) product in each run is randomized or pre-assigned in a mixedarrangement.

Method Parameter Main Alternate parameters Franz Cells Franz Cellsmembrane: durapore 0.45 μm, membrane: durapore 0.45 μm, HVLP02500HVLP02500 ring diameter 15 mm diamèter 15 mm surface: 1.767 mm″ surface:1.767 mm″ thickness: 3.2 mm thickness: 1.63 mm Gel Volume: 565.44 mm″gel Volume: 288.02 mm″ receiving media volume: 12 ml Volume mediarecptor: 7.5 ml Ethanol Water 50/50 ETOH/water 50/50 600 rpm 600 rpmAssay Assay UPLC HPLC Concentrations from 3 Concentrations 5 μg/ml to100 μg/ml μg/ml to 200 μg/ml

The slope comparison test recommended by the FDA is performed andprovides the evidence of the reproducibility of the IVRT method.

The two different formulations of the testosterone gel products, Table1, are applied on 12 cells of the modified Franz-Cell apparatus system:6 cells for reference product (R) and 6 cells for test product (T), asdepicted in FIG. 13 . The two gel products, Testosterone Nasabol Gel 4%,lot #E10-007, and TBS1A Testosterone Nasal Gel 4%, lot #IMP 11002, aredescribed in Example 6 and designated as 4% TSA-1A and TBS1.

TABLE 1 TBS-1A 4% Material TBS1 (A) Dimethyl isosorbide 0 25.0Diethyleneglycol ethyl 0 10.0 ether Povidone 0 3.0 Copovidone 0 2.0Hydroxypropyl 0 0.5 cellulose Testosterone 4.0 4.0 micronized Castor oil88.0 50.5 Labrafil M1944CS 4.0 0 Colloidal silicon 4.0 5.0 dioxide Water0 0 Total 100.0 100.0

Samples are collected at 1, 2, 3, 4, 5 and 6 hours and are tested.

Franz Cell Apparatus Position Layouts for Comparison Testing

The Release Rates (slope) from the six cells of T-product and from theother six cells of the

R-product are obtained. A 90% Confidence Interval (CI) for the ratio(T/R) of median release rates is computed.

A table with six rows and seven columns is generated and referenceslopes (RS) are listed across the first row and test slopes (TS) arelisted down the first column of Table 2. Individual T/R ratios (30)between each test slope and each reference slope are computed and thecorresponding values are entered in the table.

TABLE 2 Calculation of T/R Ratios Slope RS1 RS2 RS3 RS4 RS5 RS6 TS1 TS1/RS 1 TS 1/RS2 TS 1/RS3 TS 1/RS4 TS 1/RS5 TS 1/ RS6 TS2 TS2/RS 1TS2/RS2 TS2/RS3 TS2/RS4 TS2/RS5 TS2/ RS6 TS3 TS3/RS 1 TS3/RS2 TS3/RS3TS3/RS4 TS3/RS5 TS3/ RS6 TS4 TS4/RS I TS4/RS2 TS4/RS3 TS4/RS4 TS4/RS5TS4/ RS6 TS5 TS5/RS 1 TS5/RS2 TS5/RS3 TS5/RS4 TS5/RS5 TS5/ RS6 TS6TS6/RS 1 TS6/RS2 TS6/RS3 TS6/RS4 TS6/RS5 TS6/ RS6

These 30 T/R ratios are ranked from lowest to highest. The sixth andtwenty-fifth ordered ratios represent low and upper limits of the 90% CIfor the ratios of median release rates.

Standard Criteria:

Test and reference product are considered to be the same if the 90% CIfalls within the limits of 75%-133.3%.

Two batches of Testosterone Nasabol Gel 4%, lot #E10-007, and TBS1ATestosterone Nasal Gel 4%, lot #IMP 11002, are tested and evaluated forsameness.

A statistical comparison is carried out by taking the ratio of releaserates from 6 cells of the reference lot #E10-007 (R) against 5 cells ofthe test batch lot #IMP 11002 (T).

During the in vitro drug releases test, the reference batch and the testbatch are applied in a randomized manner on the cells on Apparatus A andB of the modified Franz Cell System.

Release Rate (slope) from five cells of the test product (T) and sixcells of the reference product (R) are compared. A 90% ConfidenceInterval (CI) for the ratio (T/R) of median release rates is computed.

The 90% Confidence Interval is represented by the sixth and twenty-fifthRelease Rate ratios

when ranked from lowest to highest. These ratios correspond to 160.77%and 202.90% respectively and do not meet the limits for sameness (CI75%-133.33%). Therefore, the two batches of Testosterone Nasabol Gel 4%,lot #E10-007 and TBS1A Testosterone Nasal Gel 4%, lot #IMP 11002 are notconsidered the same.

Two gel products, Testosterone Nasabol Gel 4%, lot #E10-007, and TBS1ATestosterone Nasal Gel 4%, lot #IMP 11002, are tested and evaluated forsameness. The Mean Release Rate (slope) for the Test lot #IMP 11002 isabout 1.8 times higher than for the Reference lot #E10-007. The twotested products are found to be not the same.

The In Vitro Release Rate (IVRT) testing results and raw data are inTables 3-8 below FIGS. 23 and 47 .

Tables 4 and 5 are graphically represented in FIGS. 38 and 39respectively.

TABLE 5 4% Gel Release Rate Comparison Testosterone Nasobol Gel 4% GelReference Lot# E10-007 Concentration of Active (μg/mL) versus TimeAmount Released (μg/mL) Calculation by Linear Regression Curve Time CellA #2 Cell A#4 Cell A#5 Cell B#1 Cell B#3 Cell B#5 Mean 1-6 % RSD 1-6 60.00  96.792 104.726 101.499  98.956  96.994 101.074 100.341 2.7120.00 143.746 153.402 151.866 148.611 146.111 152.389 149.356 2.6180.00 181.187 191.204 190.149 185.651 182.536 188.818 186.591 2.2240.00 206.803 219.307 216.557 214.046 212.670 218.650 214.672 2.2300.00 234.373 243.717 243.534 239.656 238.437 241.174 240.165 1.5360.00 253.244 262.615 261.716 259.500 255.210 263.639 259.321 1.6Actual Amont of Active Released (μg/cm²) versus Time^(0.5) AmountReleased (μg/cm²) Cell A#2 Cell A#4 Cell A#6 Cell B#1 Cell B#3 Cell B#5Mean 1-6 % RSD 1-6 Time^(0.5)  7.71 657.294 711.172 689.258 672.003672.247 686.372 681.391 2.7 10.95 1003.536 1071.352 1060.212 1037.1861020.219 1063.304 1042.635 2.6 13.42 1298.462 1371.463 1382.858 1330.7661308.915 1353.934 1337.750 2.2 15.49 1523.682 1616.405 1596.093 1576.1201565.197 1609.943 1581.240 2.2 17.32 1769.419 1844.221 1841.242 1810.5961800.351 1824.766 1815.099 1.5 18.97 1963.883 2041.513 2032.959 2013.1631981.718 2045.561 2013.135 1.7 Slope 116.80 119.04 120.10 119.69 118.02129.59 119.04 1.2 R² 0.9998 0.9997 0.9996 0.9996 0.9992 0.9997 0.99950.0

TABLE 6 Comparison Study Franz Cell Release Rate Comparison R -Reference Lot# E10-007  Testosterone Nasabol Gel 4% Gel T - Test Lot#IMP 11002    TBS1A Testosterone Nasal Gel 4% R T 116.80 119.04 120.10119.69 118.02 120.59 242.85 2.0792 2.0401 2.0221 2.0290 2.0577 2.0138187.78 1.6077 1.5775 1.5635 1.5689 1.5911 1.5572 217.83 1.8650 1.82991.8137 1.8200 1.8457 1.8064 239.55 2.0509 2.0123 1.9946 2.0014 2.02971.9865 213.29 1.8261 1.7918 1.7759 1.7820 1.8072 1.7687 Note: Test LotVial# B#6 at 2 hour was missing injection. Comparison calculated by 5 ×6 = 30 individual T/R ratios, and the limits of 90% would be sixth andtwenty-fifth order individual T/R ratios.

TABLE 7 Sixth Ordered Ratio: 160.77% Twenty-fifth Ordered Ratio: 202.90%Test and reference products are considered to be the “same” if the 90%CI falls within the limits of 75%-133.33%.

TABLE 8 Amount of Active Released (μg/cm²) Time^(0.5) Lot# IMP11002 Lot#E10-007 7.75 807.400 681.391 10.95 1360.268 1042.635 13.42 1922.0421337.75 15.49 2378.231 1581.24 17.32 2816.161 1815.099 18.97 3285.3012013.135

TABLE 9 In Vitro release Rate Testing Products: TBS1A Testosterone NasalGel 4% and Testosterone Nasobol Gel 4% Objective: Release ratecomparison between the two testosterone gel products. Side SampleInformation Release Rate Results Reference Testosterone Nasobol Gel 4%Average slope: 119.87 μg/cm² · min^(−0.5) Batch The reference Lot#E10-007 RSD of Slopes: 1.8% Expiry date: N/A R² of Lowest Linearity:0.9995 Diteba Sample ID: CSB-SPL-00200 Number of Cells: 6 Position ofCells: System (1) A#2, #4, #6; System (2) B#1, #3, #5 Test TBS1ATestosterone Nasal Gel Average slope: 300.02 μg/cm² · min^(−0.5) Batch4% RSD of Slopes: 9.3% The test batch (Lot #IMP R² of Lowest Linearity:0.9995 11001) Expiry date: N/A Diteba Sample ID: CSB-SPL-00209 Number ofCells: 6 Position of Cells System (1) A#1, #3, #5; System (2) B#2, #4,#6 Comparison Results Release Rate Comparison Comparison Limits: 75.00%to 1.33.33% Stage One  8^(th) ordered ratio: 228.50% 29^(th) orderedratio: 264.03% Stage Two 110^(th) ordered ratio: N/A 215^(th) orderedratio: N.A

Example 12 A Phase-1 Open Label, Balanced, Randomized, Crossover, TwoGroups, Two-Treatments, Two-Period, Pilot Study in Healthy Male Subjects

A phase-1 open label, balanced, randomized, crossover, two groups,two-treatments, two-period, pilot study in healthy male subjects todetermine the feasibility of a multiple dose dispenser for testosteroneintranasal gel as measured by pharmacokinetics

Testosterone replacement therapy aims to correct testosterone deficiencyin hypogonadal men. Trimel BioPharma has developed an intranasaltestosterone gel (TBS-1) as alternative to the currently availabletestosterone administration forms. To date, a syringe was used todeliver TBS-1 in clinical studies. Trimel identified a multiple dosedispenser intended for commercial use. The purpose of this study was todemonstrate the relative performance of the multiple dose dispenser incomparison to the syringe used previously in clinical trials.

This was an open label, balanced, randomized, crossover, two-group,two-treatment, two-period, pharmacokinetic study of TBS-1 testosteronenasal gel in healthy, male subjects aged 18 to 28. Treatment consistedof 4.5% TBS-1 testosterone gel as a single dose of 5.5 mg oftestosterone per nostril, delivered using either a syringe or themultiple dose dispenser, for a total dose of 11.0 mg given at 21:00hours. Prior to first administration, subjects were admitted to the unitfor blood sampling in order to determine a baseline testosteroneprofile. Wash-out between drug administrations was at least 48 hours.

All subjects completed the study successfully and treatment was welltolerated.

The total exposure to testosterone as estimated by the mean area underthe serum concentration-time curve (AUC₀₋₁₂ in ng·hr/dL), is higherafter TBS-1 administration using the dispenser or syringe thanendogenous levels alone (7484 and 7266, respectively, versus 4911ng*h/dL. Mean C_(max) is higher after administration with the dispenserthan after administration using a syringe (1028 versus 778.8 ng/dL,respectively). T_(max) occurs earlier following administration using thedispenser compared to the syringe (2.75 versus 5.6 hours, respectively.Thus, testosterone absorption seems to be faster with the multiple dosedispenser than with a syringe, but the total absorbed amount is similar.Also, in previous studies the syringe Tmax obtained in patient wascloser to 1.0 or 2.0 hours.

When plotting probability density of the log ratio of testosteronelevels reached with the multiple dose dispenser over levels reached withthe syringe as shown in FIG. 3 , no significant difference wasdemonstrated for either AUC₀₋₁₂ or C_(max) within the lower and upperlimit of the 95% confidence intervals. There is a trend toward adifference for C_(max). However, this data does not confirmbioequivalence at a confidence interval level of 90% for either AUC₀₋₁₂or C_(max). If the trends found here are confirmed in a larger data set,the routes of administration would be almost equivalent for AUC₀₋₁₂, butt for C_(max) further investigation may be required as the Cmax/tmaxprofile obtained in volunteers does not seem to match the one obtainedin patients.

Testosterone as a Treatment for Hypogonadism

Endogenous androgens are responsible for the normal growth anddevelopment of the male sex organs as well as promoting secondary sexcharacteristics including the growth and maturation of the prostate,seminal vesicles, penis, and scrotum; the development of male hairdistribution, such as beard, pubic, chest, and axillary hair, laryngealenlargements, vocal cord thickening, alterations in body musculature,and fat distribution.

Hypogonadism in men is characterized by a reduced concentration of serumtestosterone resulting in signs and symptoms that may include decreasedlibido, erectile dysfunction, decreased volume of ejaculate, loss ofbody and facial hair, decreased bone density, decreased lean body mass,increased body fat, fatigue, weakness and anaemia.

The causes of hypogonadism can be primary or secondary in nature. Inprimary hypogonadism (congenital or acquired) testicular failure can becaused by cryptorchidism, bilateral torsion, orchitis, vanishing testissyndrome, orchidectomy, Klinefelter's syndrome, chemotherapy, or toxicdamage from alcohol or heavy metals. These men usually have low serumtestosterone levels and serum gonadotropin levels (FSH, LH) above thenormal range.

In secondary hypogonadism (Hypogonadotropic Hypogonadism (congenital oracquired)) the defects reside outside the testes, and are usually at thelevel of the hypothalamus or the pituitary gland. Secondary hypogonadismcan be caused by Idiopathic Gonadotropin or LHRH deficiency, orpituitary hypothalamic injury from tumors, trauma, or radiation. Thesemen have low serum testosterone levels but have serum gonadotropinlevels in the normal or low ranges.

Testosterone hormone therapy is indicated as a hormone replacementtherapy in males for conditions associated with a deficiency or absenceof endogenous testosterone. The currently available options foradministration of testosterone are oral, buccal, injectable, andtransdermal.

Trimel BioPharma has developed an intranasal testosterone gel (TBS-1) asa hormone replacement therapy for the treatment of male hypogonadism.The nasal mucosa offers an alternative route of administration that isnot subjected to first pass metabolism, has high permeability, withrapid absorption into the systemic circulation. The advantages of thetestosterone intranasal gel when compared to other formulations includeease of administration and no transference of testosterone to otherfamily members.

Investigational Medicinal Product

The investigational medicinal product in this trial was TBS-1, anintranasal testosterone dosage form. A description of its physical,chemical and pharmaceutical properties can be found in theInvestigator's Brochure.

Summary of Non-Clinical and Clinical Studies

Summary of Non-Clinical Studies

An overview of the pharmacology, toxicology and preclinicalpharmacokinetics of different testosterone preparations andadministration routes is provided in the Investigator's BrochureProduct-specific repeat dose toxicity and tolerance studies have beenperformed in ex vivo models and in different animal species.

Summary of Previous TBS-1 Clinical Studies

To date, Trimel has completed four Phase II clinical trials inhypogonadal men. The most recently conducted study, TBS-1-2010-01, isdescribed below and the other studies are summarized in theInvestigator's Brochure.

The objective of study TBS-1-2010-01 is to examine the efficacy andtolerability of 4.0% and 4.5% TBS-1 testosterone gel in hypogonadal men.In this study, TBS-1 is administered using a syringe, not the commercialmultiple dose dispenser. The doses and dosing regimens that were used instudy TBS-1-2010-01 are described in Table 1 below.

The results from all treatment groups met the FDA criteria for efficacy;defined as that at least 75% of subjects should achieve an average totalT concentration (C_(avg)) in the normal range, a 24 hour C_(avg) value≥300 ng/dL and ≤1050 ng/dL.

TABLE 1 Summary of previous TBS-1 studies C_(avg) (% of subjects withC_(avg) within the Dosing regimen Total daily dose reference range) 13.5 mg of TBS-1 (4.5%) BID   27 mg/day  419 ng/dL (100%)  10.0 mg ofTBS-1 (4.0%) TID   30 mg/day 413 ng/dL (87%) 11.25 mg of TBS-1 (4.5%)TID 33.75 mg/day 396 ng/dL (85%)Summary of Benefits and Risks to SubjectsBenefits

Testosterone replacement therapy for hypogonadal men should correct theclinical abnormalities of testosterone deficiency. Since this was aPhase I study enrolling normal healthy men between the ages of 18-45,for a short period of time, it was not anticipated that these volunteerswould directly benefit by taking part in this study. Volunteers werefinancially compensated for their participation.

Risks

The risk to the subject by participating in this study was considered tobe minimal. Testosterone replacement therapy is indicated for thetreatment of hypogonadism and TBS-1 has been administered to over 100men with minimal side effects.

As TBS-1 is an investigational drug that is in clinical development, thecomplete side effect profile was not fully known. Epistaxis, nasalcongestion, nasal discomfort, nasal dryness and nasal inflammation havebeen reported following use of TBS-1. Side effects from approved(prolonged) testosterone replacement therapy include elevated liverenzymes (alanine aminotransferase, aspartate aminotransferase),increased blood creatine phosphokinase, increase in prostatic specificantigen, decreased diastolic blood pressure, increased blood pressure,gynecomastia, headache, increased hematocrit/hemoglobin levels, hotflushes, insomnia, increased lacrimation, mood swings, smell disorder,spontaneous penile erection, and taste disorder.

The main benefit of the intranasal drug delivery route is that with thismethod many of the different disadvantages observed with other productswould not be expected. This would include skin-to-skin transfer,stickiness, unpleasant smell (gels), skin irritation (patches), elevatedDHT (patches and oral), injection pain and high T and DHT peaks(intramuscular injection), food interaction (oral).

Trial Rationale

Trimel identified a multiple dose dispenser that was intended as thecommercial dispenser to be used in this clinical trial program. To date,a syringe has been used to deliver TBS-1 in the previous clinicaltrials. The purpose of this study was to demonstrate the comparabilityof the pharmacokinetic results obtained with a multiple dose dispenseror a syringe.

REFERENCES

-   1. Nasobol® Investigator Brochure Release Date 19 Aug. 2010, Edition    No: 5.-   2.    http://www.androgel.com/pdf/500122-00127_Rev_1E_Sep_2009_FPI_with_MedGuide.pdf    (Last accessed on 6 Sep. 2010).-   3. http://www.mattern-pharmaceuticals.com/downloads/Nasobol.pdf    (Last accessed on 6 Sep. 2010).-   4.    http://www.medicines.org.uk/EMC/medicine/22159/SPC/Testim+Gel/(Last    accessed on 6 Sep. 2010).    Study Objectives

The primary study objective is to compare a pharmacokinetic profile oftestosterone after administration of TBS-1 using two differentdispensers in healthy male subjects.

The secondary objective is to assess the safety of TBS-1.

Investigational Plan

Overall Study Design and Plan

This is an open label, balanced, randomized, crossover, two-group,two-treatment, two-period, pharmacokinetic study of testosterone nasalgel formulation in healthy, adult, male human subjects. The study eventschedule is summarized in Section?????in Table 2.

Healthy male volunteers, aged 18 to 45 years (inclusive) were screenedfor this study. The goal was to randomize 12 male subjects for thestudy.

There was a washout period of 6 days between each drug administration.

Discussion of Study Design

As this is a relatively small Phase I PK study with the intent tocompare a pharmacokinetic profile of testosterone after administrationof TBS-1 from two different dispensers in healthy male subjects, a truesample size calculation is not performed. Based on typical early-stage,pharmacokinetic studies, groups of 6 subjects per cohort are sufficientfor an acceptable description of the pharmacokinetic parameters aftersingle dose administration.

Selection of Study Population

Inclusion Criteria

The following eligibility assessments have to be met for subjects to beenrolled into the study:

-   -   1. Healthy male human subjects within the age range of 18 to 45        years inclusive    -   2. Willingness to provide written informed consent to        participate in the study    -   3. Body-mass index of ≤35 kg/m²    -   4. Absence of significant disease or clinically significant        abnormal laboratory values on laboratory evaluations, medical        history or physical examination during screening    -   5. Normal otorhinolaryngological examination    -   6. Non-smokers for at least six months    -   7. Comprehension of the nature and purpose of the study and        compliance with the requirement of the protocol        Exclusion Criteria

A subject is not eligible for inclusion in this study if any of thefollowing criteria applied:

-   -   1. Personal/family history of allergy or hypersensitivity to        testosterone or related drugs    -   2. Past history of anaphylaxis or angioedema    -   3. Any major illness in the past three months or any clinically        significant ongoing chronic medical illness e.g. congestive        heart failure, hepatitis, pancreatitis etc.    -   4. Presence of any clinically significant abnormal values during        screening e.g. significant abnormality of Liver Function Test        (LFT), Renal (kidney) Function Test (RFT), etc.    -   5. Hemoglobin <13 g/dl and Hematocrit >52% during screening    -   6. Any cardiac, renal or liver impairment, any other organ or        system impairment    -   7. History of seizure or clinically significant psychiatric        disorders    -   8. Presence of disease markers for HIV 1 and/or 2, Hepatitis B        and/or C virus    -   9. History of nasal surgery, specifically turbinoplasty,        septoplasty, rhinoplasty, (“nose job”), or sinus surgery    -   10. Subject with prior nasal fractures    -   11. Subject with active allergies, such as rhinitis, rhinorrhea,        or nasal congestion    -   12. Subject with mucosal inflammatory disorders, specifically        pemphigus, or Sjogren's syndrome    -   13. Subject with sinus disease, specifically acute sinusitis,        chronic sinusitis, or allergic fungal sinusitis    -   14. History of nasal disorders (e.g. polyposis, recurrent        epistaxis (>1 nose bleed per month), abuse of nasal        decongestants) or sleep apnea    -   15. Subject using any form of intranasal medication delivery,        specifically nasal corticosteroids and oxymetazoline containing        nasal sprays (e.g. Dristan 12-Hour Nasal Spray)    -   16. History of asthma and/or on-going asthma treatment    -   17. Regular drinkers of more than three (3) units of alcohol        daily (1 unit=300 ml beer, 1 glass wine, 1 measure spirit), or        consumption of alcohol within 48 hours prior to dosing and        during the study.    -   18. Volunteer demonstrating a positive test for alcohol        consumption (using breath alcohol analyzer) at the time of        check-in during the admission periods.    -   19. History of, or current evidence of, abuse of alcohol or any        drug substance, licit or illicit    -   20. Volunteers demonstrating a positive test for drugs of abuse        in urine (Opiates, Benzodiazepines, Amphetamines, THC and        cocaine) at the time of check-in during admission periods    -   21. Inaccessibility of veins in left and right arm    -   22. Receipt of any prescription drug therapy within four weeks        of the first admission period.    -   23. Difficulty in abstaining from OTC medication (except        occasional paracetamol/aspirin) for the duration of the study    -   24. Volunteers demonstrating serum PSA 4 ng/ml    -   25. Participation in any other research study during the conduct        of this study or 30 days prior to the initiation of this study.    -   26. Blood donation (usually 550 ml) at any time during this        study, or within the 12 week period before the start of this        study.        Removal of Patients from Therapy or Assessment

All 12 subjects who enroll, complete the study successfully, and nosubjects are replaced.

Treatments

Treatments Administered

For the drug administration, subjects are instructed on how TBS-1 isapplied intranasally with the pre-filled syringes or the multiple dosedispensers. Self-administration of TBS-1 is monitored by the studypersonnel. Each subject is instructed not to sniff or blow his nose forthe first hour after administration.

TABLE 2 Treatment schedule BASELINE PERIOD I PERIOD II Day 1/2 Day 2/3Day 4/5 Subject Time Time Time GROUP number 21:00-09:00 21:00-09:0021:00-09:00 A 1-6 12 hour baseline TREATMENT 1 TREATMENT 2 T profile B 7-12 12 hour baseline TREATMENT 2 TREATMENT 1 T profile

Treatment 1 consists of TBS-1 syringes that are pre-filled with 4.5%testosterone gel to deliver a single dose of 5.5 mg of testosterone pernostril, for a total dose of 11.0 mg that is administered at 21:00 hours(±30 minutes) on Day 2 of Period I for Group A and Day 4 of Period IIfor Group B.

Treatment 2 consists of a TBS-1 multiple dose dispensers that arepre-filled with 4.5% testosterone gel to deliver a single dose of 5.5 mgof testosterone per nostril, for a total dose of 11.0 mg that isadministered at 21:00 hours (±30 minutes) on Day 2 of Period I for GroupB and Day 4 of Period II for Group A.

Identity of Investigational Product(s)

The investigational product in this trial is TBS-1, an intranasaltestosterone dosage form.

Study medication consists of TBS-1 gel and is packed either in a singleuse syringe that is designed to expel 125 μl of gel, with two syringespackaged per foil pouch, or in a multiple dose dispenser that isdesigned to expel 125 μl of gel/actuation.

Study medication is dispensed by the study pharmacist who prepares theindividual study kits which contained two syringes in a pouch or themultiple dose dispenser.

Method of Assigning Patients to Treatment Groups

Treatment assignment is determined according to the randomizationschedule at the end of Visit 1. Subjects who met the entry criteria areassigned randomly on a 1:1 basis to one of the two treatment groups(Group A or Group B). The randomization is balanced and the code is keptunder controlled access. The personnel that are involved in dispensingof study drug is accountable for ensuring compliance to therandomization schedule.

Selection and Timing of Dose

As healthy males have endogenous testosterone levels that fluctuate witha circadian rhythm which peaks in the early morning, it is decided todose the study medication at night.

Blinding

This is an open-label study for both the subjects and the investigator,as the physical differences in the intranasal dosing dispensers preventblinding.

Prior and Concomitant Therapy

None of the subjects use prescription medication immediately prior to,during or the 2 weeks after the study. One subject receives a singledose of paracetamol (2 tablets of 500 mg) just before discharge on themorning after the baseline visit (before administration of any studymedication). There are no other reports of medication use.

Treatment Compliance

All subjects receive both doses of study medication according to theinstructions and are monitored by study personnel for one-hourpost-dosing to assure conformity to the TBS-1 instructions. All subjectsremain in the clinic during the 12-hour PK sampling time period; duringwhich they are monitored closely.

Screening

The screening visit (visit 1) takes place at a maximum of 21 days beforethe first study day. After giving informed consent, the suitability ofthe subject for study participation is assessed at screening whichconsists of the following items:

-   -   Medical history    -   Physical examination and Vital Signs.    -   A fasting blood sample is taken to determine the following:        Complete Blood Count, Chemistry profile; testing for HBV, HCV,        HIV and PSA.    -   Urinalysis, urine drug screen, and Breath Alcohol Testing.    -   An otorhinolaryngological nasal endoscopic examination is        performed by an ENT specialist.

Subjects meeting all of the inclusion and no exclusion criteria areenrolled into the study and are randomized into one of two treatmentgroups (1 or 2).

Study Days

Subjects are admitted to the clinical research centre at 19:30 hours onDay 1 (Visit 2, baseline), 2 (Visit 3, Period 1) and 4 (Visit 4, Period2). After check-in tests for drug-abuse and alcohol consumption areperformed. Vital signs are recorded and subjects are questioned aboutchanges in their health.

During Visit 2, a 12 hour baseline testosterone profile is measured.Blood for the 12 hour baseline testosterone profile is drawn accordingto the following schedule: first sample at 20:45 hours and then at 0.33,0.66, 1.00, 1.50, 2.00, 3.00, 4.00, 5.00, 6.00, 8.00, 10.00, and 12.00hours relative to 21:00 time point (a total of 13 samples). On Day 2vital signs are measured and safety parameters (symptoms, AEs) recordedbefore check-out.

Dosing is performed on the evenings of Day 2 and 4, at 21:00 hr. Beforedosing an ENT examination is performed and a pre-dose, baseline serumtestosterone blood sample is drawn. After dosing, a 12 hour testosteronePK profile is measured. The blood samples are drawn according to thefollowing schedule after the 21:00 hour dosing: 0.33, 0.66, 1.00, 1.50,2.00, 3.00, 4.00, 5.00, 6.00, 8.00, 10.00, and 12.00 hr time points (atotal of 13 samples per period).

On Day 3 and 5 vital signs are measured, ENT examination are performedand safety parameters are recorded (symptoms, AEs) after the last PKsampling and before check-out. On Day 5 a final examination isperformed, consisting of a general physical examination and clinicallaboratory investigation (Complete Blood Count, Chemistry profile andUrinalysis).

Pharmacokinetic Sampling

Blood samples for analysis of testosterone levels are collected in 4 mlstandard clotting tubes using an intravenous cannula. Tubes are left toclot for 30-45 minutes. Samples are centrifuged within one hour at 2000g for 10 minutes at 4° C. The serum is then transferred directly to twoaliquots of 1 ml each and frozen at −40° C.

Safety

Blood samples for hematology are collected in 4 ml EDTA tubes and sentto the hematology laboratory of the Leiden University Medical Center(LUMC) for routine analysis. Blood samples for blood chemistry arecollected in 4 ml Heparin tubes and sent to the clinical chemistrylaboratory for routine analysis.

Drug Concentration Measurements

Frozen serum samples for PK analysis are stored in the freezer at −40°C. and are shipped on dry ice to the laboratory, at the end of thestudy. Samples are analyzed using a validated LC-MS method for thedetermination of testosterone levels. It is not possible to discriminateendogenous and exogenous testosterone from each other using this method.

Quality Assurance

The study is conducted in compliance with the pertaining CHDR StandardOperating Procedures and CHDR's QA procedures.

Calculation of Pharmacokinetic Parameters

A validated LC-MS/MS method is employed to determine serum testosterone.All samples from study participant completing both the periods areanalyzed.

Incurred sample reanalysis is performed:

-   -   C_(min), C_(max), and t_(max) actual measured values. Values are        determined relative to the testosterone administration time in        treated subjects.    -   Area under the concentration curve (AUC) is estimated for the 0        to 12 hour time interval using the trapezoidal rule.    -   Significance is evaluated using the t-test. Additional        exploratory analyses of PK parameters could be performed as        necessary.

The relative pharmacokinetic profile of the pre-filled syringe and themultiple dose dispenser is determined using the AUC_(0-12h) andCmax_(0-12h) corrected for the endogenous serum testosteroneconcentration. For bioequivalence, the relative mean of the dispenser tothe pre-filled syringe using log transformed data for AUC_(0-12h) andCmax_(0-12h) is corrected for the endogenous serum testosteroneconcentration, is determined to be between 80% to 125%.

Analysis of Safety Parameters

The Day 5 close-out findings is compared to the screening results andclinically significant changes were to be identified in the following:

-   -   1. Vital Signs and Adverse Events: Blood Pressure, Body        Temperature, Respiratory Rate, Heart Rate.    -   2. Otorhinolaryngological examination with the nasal tolerance        data presented in summary tables.    -   3. Complete Blood Count: white blood count, hemoglobin and        hematocrit.    -   4. Clinical chemistry profile: sodium, potassium, chloride,        glucose, urea, creatinine, calcium, phosphate, uric acid, total        bilirubin, albumin, AST, ALT, ALP, GGT, CK and cholesterol.    -   5. Urinalysis.        Determination of Sample Size

As this is a relatively small Phase I PK study with the intent tocompare a pharmacokinetic profile of testosterone after administrationof TBS-1 from two different dispensers in healthy male subjects, a truesample size calculation is not performed.

Subjects

26 Subjects are enlisted

-   -   2 subjects are not screened due to planning problems    -   1 subject is not screened because he does not have a general        practitioner

23 Subjects are screened

-   -   3 screening failures due to ENT abnormalities    -   1 screening failure due to positive hepatitis B test    -   1 screening failure due to positive hepatitis C test

18 Subjects passed screening

-   -   12 subjects are randomized and completed the study    -   1 subject is cancelled before the baseline visit due to        concurrent illness    -   5 subjects are reserves, but not needed

No subjects discontinue after randomization.

Efficacy Evaluation

Data collected is used in the analysis. This yields three PK curves of12 hours each, one without treatment (baseline), and one each afteradministration of TBS-1 using the multiple dose dispenser or syringe.

Demographic Characteristics

Subject demographics are summarized in Table 4 below.

TABLE 4 Subject demographics Variable N MEAN STD MIN MAX Age (yrs) 1223.4 3.0 18 28 BMI (kg/m²) 12 23.55 2.45 20.9 28.4 Height (cm) 12 184.438.46 173.5 197.0 Weight (kg) 12 80.08 9.76 63.2 98.2Measurements of Treatment Compliance

The nasal gel is self-administered by subjects. All administrations aresuccessful.

Efficacy Results and Tabulations of Individual Patient Data

FIG. 24 shows the individual serum testosterone levels per occasion(baseline without medication, TBS-1 using the multiple dose dispenserand TBS-1 using syringes), where T=0 occurred at 21:00 hours clock time.FIG. 24 shows the individual and median testosterone concentrationversus time grouped by treatment.

All subjects have testosterone levels within the normal range (24 hourC_(mean)≥300 ng/dL and ≤1050 ng/dL). The baseline curves clearly showthe slow circadian fluctuations in testosterone levels that are expectedin a young, healthy population with the highest levels in the earlymorning.

Although dose and volume of TBS-1 that is administered is exactly thesame for both forms of administration, the graphs in FIGS. 15 and 16suggest that there are differences in pharmacokinetic profile.

Pharmacokinetic Parameters

The following primary pharmacokinetic parameters, per occasion, arecalculated:

-   -   AUC₀₋₁₂: Area under the serum concentration-time curve        (ng·hr/dL) for each occasion from 21:00 to 9:00 hrs, is        calculated using the linear trapezoidal method.    -   C_(mean): Mean concentration (ng/dL) during each occasion from        21:00 to 9:00 hrs, is calculated as AUC_0-12/12.    -   C_(max): Maximum is observed concentration (ng/dL) during each        occasion.    -   C_(min): Minimum is observed concentration (ng/dL) during each        occasion.    -   t_(max): Time (hr) at which C_(max) is observed.

Tables 5 to 7 below summarize the primary pharmacokinetic parameters forendogenous testosterone during the baseline visit when no treatment isadministered, for TBS-1 when administered using the multiple dosedispenser, and for TBS-1 when administered using a syringe.

Testosterone, Baseline, No Treatment

TABLE 5 Testosterone, no treatment Parameter Mean SD Median Min Max NAUC₀₋₁₂ 4911 1156 4726 3337 7164 12 t_(max) 8.833 3.486 10.0 2.0 12 12C_(max) 514.2 117.5 480.0 384.0 746 12 C_(min) 298.6 89.01 308.0 134.0453 12 C_(mean) 409.0 96.4 392.8 278.1 597 12 AUC₀₋₁₂ in ng*hr/dL;t_(max) in hours; C_(max), C_(min) and C_(mean) in ng/dLTestosterone, TBS-1 Multiple Dose Dispenser

TABLE 6 Testosterone, TBS-1 multiple dose dispenser Parameter Mean SDMedian Min Max N AUC₀₋₁₂ 7484 1798 7347 4847 11350 12 t_(max) 2.7513.961 1.25 0.3333 12 12 C_(max) 1028 283.1 970.5 645 1440 12 C_(min)337.9 119.7 328.5 145 565 12 C_(mean) 623.6 149.9 612.3 403.9 945.7 12AUC₀₋₁₂ in ng*hr/dL; t_(max) in hours; C_(max), C_(min) and C_(mean) inng/dLTestosterone, TBS-1 Syringe

TABLE 7 Testosterone, TBS-1 syringe Parameter Mean SD Median Min Max NAUC₀₋₁₂ 7266 1360 7237 5186 9371 12 t_(max) 5.612 4.736 5.0 0.667 12 12C_(max) 778.8 144.1 754.5 543 1100 12 C_(min) 355.9 66.96 337.0 291 49812 C_(mean) 605.4 113.2 603.1 432.2 780.9 12 AUC₀₋₁₂ in ng*hr/dL;t_(max) in hours; C_(max), C_(min) and C_(mean) in ng/dL

The listing of individual primary pharmacokinetic parameters is includedin Table 7A.

TABLE 7A Efficacy Data Individual PK Parameters Individual PK parameters0-12 hrs for each occasion Subject Occasion Treatment AUC_0-12t_maxC_max C_mean C_min 1 1 No Treatment 5722 10.0000 600 476.9 321 1 2 TBS-1mdd 9394 12.0000 1070 782.9 340 1 3 TBS-1 syringe 7802 12.0000 840 650.1400 2 1 No Treatment 3731 10.0000 388 310.9 242 2 2 TBS-1 syringe 73671.5000 779 613.9 333 2 3 TBS-1 mdd 7592 0.3333 1420 632.7 386 3 1 NoTreatment 4771 3.0000 498 395.4 332 3 2 TBS-1 mdd 6056 0.6667 645 504.7395 3 3 TBS-1 syringe 7107 5.0000 691 592.3 312 4 1 No Treatment 71642.0000 746 597.0 453 4 2 TBS-1 syringe 8639 6.0000 837 720.0 498 4 3TBS-1 mdd 8370 0.3333 1440 697.5 500 5 1 No Treatment 3337 10.0000 384278.1 134 5 2 TBS-1 mdd 4847 0.3500 1280 403.9 145 5 3 TBS-1 syringe5439 1.0000 725 453.3 292 6 1 No Treatment 3673 10.0000 422 305.2 166 62 TBS-1 syringe 5186 10.0200 543 432.2 304 6 3 TBS-1 mdd 5851 1.0000 715487.6 325 7 1 No Treatment 4681 12.0000 456 390.1 324 7 2 TBS-1 syringe6250 12.0000 661 520.8 291 7 3 TBS-1 mdd 6503 1.5000 881 541.2 159 8 1No Treatment 4632 12.0000 473 386.0 295 8 2 TBS-1 mdd 7102 1.5000 813591.9 332 8 3 TBS-1 syringe 8529 0.6667 1100 710.7 343 9 1 No Treatment4222 12.0000 481 351.8 287 9 2 TBS-1 mdd 11350  3.0000 1350 945.7 276 93 TBS-1 syringe 6992 12.0000 730 582.7 341 10 1 No Treatment 650310.0000 718 541.9 397 10 2 TBS-1 syringe 9371 5.0000 874 780.9 445 10 3TBS-1 mdd 8747 10.0000 820 728.9 565 11 1 No Treatment 5541 5.0000 525461.7 353 11 2 TBS-1 mdd 7823 2.0000 848 651.9 315 11 3 TBS-1 syringe8550 1.5000 898 710.6 408 12 1 No Treatment 4950 10.0000 479 412.5 27912 2 TBS-1 syringe 5962 0.6667 668 496.8 304 12 3 TBS-1 mdd 6171 0.33331060 514.2 317 mdd - multiple dose dispenser

Total testosterone exposure is estimated by the mean area under theserum concentration-time curve (AUC₀₋₁₂ in ng·hr/dL) is higher afterTBS-1 administration using the dispenser or syringe than endogenouslevels alone (7484 and 7266, respectively, versus 4911 ng*h/dL). Betweenthe methods of administration, the difference in mean AUC₀₋₁₂ is small.The significance of this difference is explored below.

Unexpectedly, mean C_(max) is higher after administration with thedispenser than when with a syringe (1028 versus 778.8 ng/dL,respectively). T_(max) occurs sooner after administration using thedispenser than after the syringe (2.75 versus 5.6 hours, respectively).Thus, after administration using the multiple dose dispenser serumtestosterone seems to be absorbed faster than with a syringe. Thesignificance of these differences is explored below.

Two subjects reach t_(max) of testosterone only 10 and 12 hours afteradministration with the dispenser. In three subjects, t_(max) is 10 and12 hours after administration with the syringe, and t_(max) is 5 and 6hours in two others. Most likely, the endogenous testosterone peakfluctuation exceeded levels that is caused by exogenous testosteroneadministration. Thus, the calculated mean t_(max) may be faster whentestosterone is dosed high enough that the peak caused by exogenousadministration exceeds the endogenous peak.

Derived Pharmacokinetic Parameters

The following derived pharmacokinetic parameters, combining results fromoccasions, are calculated:

-   -   AUC_(0-12_drug): difference between AUC₀₋₁₂ after treatment        (syringe or dispenser) and no treatment (baseline occasion)    -   C_(max_drug): difference between C_(max) after treatment        (syringe or dispenser) and the observed concentration at t_(max)        in absence of treatment (baseline occasion)    -   Ratio AUC_(0-12_drug): % ratio between AUC_(0-12_drug) using        dispenser and syringe    -   Ratio C_(max_drug): % ratio between C_(max_drug) using dispenser        and syringe    -   Mean and uncertainty (95%, 90% and 80% confidence interval) of        the log of Ratio AUC_(0-12_drug)    -   Mean and uncertainty (95%, 90% and 80% confidence interval) of        the log of Ratio C_(max_drug)        Testosterone Level Using TBS-1, Baseline Subtracted

Tables 8 and 9 below show the AUC and C_(max) for the different TBS-1delivery methods after subtracting baseline levels of testosterone.

TABLE 8 Testosterone level using TBS-1 multiple dose dispenser, baselinesubtracted Parameter Mean SD Median Min Max N AUC₀₋₁₂_drug 2573.0 1679.02211 1207 7126 12 C_(max)_drug  630.8  314.7  534  102 1111 12

TABLE 9 Testosterone level TBS-1 syringe, baseline subtracted ParameterMean SD Median Min Max N AUC₀₋₁₂_drug 2356.0 900.9 2219 1012 3897 12C_(max)_drug  379.9 177.1  357  121  782 12Testosterone Level TBS-1 Dispenser Over Syringe Ratio

Table 10 below shows the ratio of serum testosterone levels that arereached with the dispenser or syringe, after subtracting baselinetestosterone levels. There is clearly a difference in C_(max) betweenthe administration forms (mean ratio dispenser over syringe C_(max)2.057), but the AUCs are comparable (mean ratio dispenser over syringeAUC 1.12).

TABLE 10 Testosterone, ratio of TBS-1 multiple dose dispenser oversyringe Parameter Mean SD Median Min Max N Ratio AUC₀₋₁₂_drug 1.1220.580 0.940 0.550 2.572 12 Ratio C_(max)_drug 2.057 1.339 1.983 0.2274.455 12 logRatio AUC₀₋₁₂_drug 0.014 0.453 −0.071 −0.598 0.945 12logRatio C_(max)_drug 0.455 0.860 0.684 −1.484 1.494 12

Table 11 below shows the log of the ratio of serum testosterone levelsthat are reached when administering using the multiple dose dispenserover syringe, after subtracting baseline testosterone levels, with 95%,90% and 80% confidence intervals.

When plotting probability density of the log ratio of testosteronelevels that are reached with the multiple dose dispenser over levelsthat are reached with the syringe as shown in FIG. 17 , no significantdifference is demonstrated for either AUC₀₋₁₂ or C_(max) within 95%confidence intervals. There is a trend toward a difference for C_(max).However, this data does not confirm bioequivalence at a confidenceinterval level of 90% for either AUC₀₋₁₂ or C_(max), as the study is notpowered for 2-one-sided tests.

TABLE 11 Testosterone TBS-1 log ratios with different confidenceintervals Parameter Mean CI (%) LLCI ULCI logRatio 0.01398 95 −0.274000.3019 AUC₀₋₁₂_drug 90 −0.2209574 0.24892 80 −0.16438 0.19234 logRatio0.45520 95 −0.09145 1.0020 C_(max)_drug 90 0.00917 0.90127 80 0.116580.79386 CI = confidence interval; log(0.8) = −0.22314; log(1.25) =0.22314Handling of Dropouts or Missing Data

No subjects drop out of the study. Blinded data review did not lead toremoval of any data points.

Extent of Exposure

The pharmacokinetic results show that exposure to testosterone is onlyhigher than the upper level of the normal range very briefly shortlyafter TBS-1 administration.

Adverse Events (AEs)

Treatment is well tolerated. There are 12 adverse event reports intotal. Three events had their onset before the first administration ofstudy medication and are therefore unrelated. Four reports of mildcomplaints such as sore throat are considered unlikely to be caused bystudy medication when considering the nature of the complaints and thetime lapse after administration. One subject reschedules one occasionbecause of gastro-intestinal complaints that are unlikely to be relatedto study medication, onset of symptoms is days after study drugadministration. Symptoms resolve without treatment.

Reports of bad smell and taste are the only complaints that areconsidered clearly related to administration of medication. Thesecomplaints are mild in intensity and could be considered a productcharacteristic rather than a medical condition. Bad smell and tastecomplaints do not lead to discontinuation of the study medication anddiminishes with repeated dosing.

Display of Adverse Events

A listing of adverse events is included in Table 12.

TABLE 12 Listing of Adverse Events Treatment Treatment action StartDiagnosis SAE related Subject Visit Symptoms Chronicity DurationSeverity TBS-1 mdd  2 3 6 APR. 2011 8:30 OROPHARYNGEAL PAIN NoneIrritated single occasion 0D01H20M mild No unlikely throat.  3 2 30 MAR.2011 12:00 HEADACHE None Headache single occasion 0D09H00M mild Nounrelated 30 MAR. 2011 21:04 APPLICATION SITE ODOUR None Smells nasty,single occasion 0D02H55M mild No definitely bad taste.  5 2 30 MAR. 201120:40 APPLICATION SITE ODOUR None It smells nasty. single occasion0D00H30M mild No definitely 30 MAR. 2011 21:15 DYSGEUSIA None Bad taste.single occasion 0D00H45M mild No definitely  8 2 13 APR. 2011 20:45CATHETER SITE RASH Removed plastic Red rash in single occasion 1D18H15Mmild No unrelated tape patch. left armpit, where cannula is placed.TBS-1 syringe  1 3 6 APR. 2011 8:30 OROPHARYNGEAL PAIN None Sore throat,single occasion 0D00H40M mild No unlikely  2 2 31 MAR. 2011 13:00AGITATION None Feeling single occasion 0D20H00M mild No unlikelyagitated.  4 2 30 MAR. 2011 20:45 APPLICATION SITE ODOUR None It smellsnasty. single occasion 0D00H20M mild No definitely  6 2 30 MAR. 201120:33 APPLICATION SITE ODOUR None It smells nasty. single occasion0D00H27M mild No definitely 10 2 18 APR. 2011 23:00 DIARRHOEA NoneNausea, single occasion 1D21H00M mild No unlikely diarrhoea. NoTreatment 11 1 13 APR. 2011 9:19 HEADACHE Paracetamol, Headache singleoccasion 0D06H41M mild No unrelated sleep. Note: mdd = multiple dosedispnenser M = Missing U = UnknownAnalysis of Adverse Events

All adverse events are considered mild and are transient. Nasaltolerance is good. Initial complaints of bad smell or taste did not leadto discontinuation of the study.

Deaths, Other Serious Adverse Events, and Other Significant AdverseEvents

There are no deaths, serious adverse events or other significant adverseevents.

Evaluation of Each Laboratory Parameter

There are no abnormal hematology, blood chemistry or urine laboratoryfindings that are considered clinically significant in the opinion ofthe investigator.

Vital Signs, Physical Findings and Other Observations Related to Safety

There are no abnormal findings in vital signs, on physical examinationsor other observations that are considered clinically significant in theopinion of the investigator.

Safety Conclusions

Treatment is well tolerated, nasal tolerance is good. All adverse eventsare considered mild and are transient. Initial complaints of bad smellor taste did not lead to study discontinuation.

Discussion and Overall Conclusions

This study compares the pharmacokinetic profile of TBS-1 testosteronenasal gel administered using a multiple dose dispenser to the profile ofTBS-1 delivery using a syringe. In order to avoid carry-over effectsthat are caused by repeated dosing, the order of administration israndomized. Prior to first administration, subjects are admitted to theunit for blood sampling in order to determine a baseline testosteroneprofile.

All 12 subjects, age range 18 to 28 years, complete the studysuccessfully. Although not assessed at screening, all subjects havebaseline testosterone levels within the normal range. Treatment is welltolerated and all reported adverse events are transient and consideredmild. Complaints of bad smell and taste are reported, although this didnot lead to discontinuation and decreased with repeated dosing.

As expected, the total exposure to testosterone (as estimated by themean area under the serum concentration-time curve (AUC₀₋₁₂)) afterTBS-1 administration using the dispenser or syringe exceed endogenouslevels. The difference in mean AUC₀₋₁₂ between the two modes ofadministration is small.

Unexpectedly, mean C_(max) is considerably higher after administrationwith the dispenser than when administering using a syringe. T_(max) isalso earlier after administration using the dispenser than after theusing the syringe. Thus, testosterone absorption seems to be faster withthe multiple dose dispenser than with a syringe, but the total absorbedamount is similar.

Two subjects reach t_(max) of testosterone only 10 and 12 hours afteradministration with the dispenser. In three subjects, t_(max) is 10 and12 hours after the syringe, and t_(max) is 5 and 6 hours in two others.Most likely, the endogenous testosterone peak fluctuation exceed levelsthat are caused by exogenous testosterone administration. Thus, thecalculated mean t_(max) may be faster when testosterone is dosed highenough that the peak caused by exogenous administration exceeds theendogenous peak.

When plotting probability density of the log ratio of testosteronelevels that are reached with the multiple dose dispenser over levelsthat are reached with the syringe, no significant difference isdemonstrated for either AUC₀₋₁₂ or C_(max) within 95% confidenceintervals. There is a trend toward a difference for C_(max). However,this data does not confirm bioequivalence at a confidence interval levelof 90% for either AUC₀₋₁₂ or C_(max). This finding may be due to thefact that the ideal positioning of the delivering tip is easier to findwith the multiple dose device than the syringe.

Also, in accordance with this Example 6, see FIGS. 23 and 24 .

The following formulations are in Table 13 used in Examples 5-7 and inFIGS. 23 and 24 .

TABLE 13 TBS1V TBS-1A 4% TBS-1A 4% Material TBS1 (vs. H20) (A) alternate(B) TBS-1A 8% Dimethyl isosorbide 0 0 25.0 15.0 25.0 Diethyleneglycolethyl ether 0 0 10.0 5.0 10.0 Povidone 0 0 3.0 3.0 3.0 Copovidone 0 02.0 2.0 2.0 Hydroxypropyl cellulose 0 0 0.5 0.5 0.5 Testosteronemicronized 4.0 4.0 4.0 4.0 8.0 Castor oil 88.0 87.95 50.5 65.5 46.5Labrafil M1944CS 4.0 4.0 0 0 0 Colloidal silicon dioxide 4.0 4.0 5.0 5.05.0 Water 0 0.05 0 0 0 Total 100.0 100.0 100.0 100.0 100.0

Example 13 A Phase 3, 90-Day, Randomized, Dose-Ranging Study, IncludingPotential Dose Titration, Evaluating the Efficacy and Safety ofIntranasal TBS-1 in the Treatment of Male Hypogonadism with SequentialSafety Extension Periods of 90 and 180 Days Investigational Product:4.5% TBS-1 Intranasal Testosterone Gel Protocol Number: TBS-1-2011-03

Synopsis

TITLE: A 90-Day, Randomized, Dose-Ranging Study, Including PotentialDose

Titration, Evaluating the Efficacy and Safety of Intranasal TBS-1 in theTreatment of Male Hypogonadism With Sequential Safety Extension Periodsof 90 and 180 Days

PROTOCOL NUMBER: TBS-1-2011-03

INVESTIGATIONAL PRODUCT: TBS-1 intranasal 4.5% testosterone gel

PHASE: 3

INDICATION: Adult male hypogonadism (primary and secondary)

OBJECTIVES:

The primary objective of the study is to determine the efficacy of 4.5%TBS-1 gel, administered as 2 or 3 daily intranasal doses of 5.5 mg pernostril, as demonstrated by an increase in the 24-hour averageconcentration (C_(avg)) of serum total testosterone to the normal range(≥300 ng/dL and ≤1050 ng/dL) in ≥75% of male subjects treated forhypogonadism. See also Exhibit C (the contents of which are incorporatedherein by reference).

The secondary objectives of this study are the following:

-   -   To determine the efficacy of 4.5% TBS-1 gel, administered 2 or 3        times daily at a dose of 5.5 mg per nostril, in achieving the        following for serum total testosterone maximum concentration        (C_(max)):        -   C_(max)≤1500 ng/dL in ≥85% of subjects,        -   C_(max) 1800 to 2500 in <5% of subjects, and        -   C_(max)>2500 ng/dL in no subjects;    -   To determine the safety and tolerability of TBS-1 after 90, 180,        and 360 days of treatment;    -   To determine the effect of TBS-1 treatment on body composition        (total body mass, lean body mass, fat mass, and percent fat);    -   To determine the effect of TBS-1 treatment on bone mineral        density (lumbar spine and hip);    -   To determine the effect of TBS-1 treatment on mood;    -   To determine the effect of TBS-1 treatment on erectile function;        and

To determine the serum concentration and pharmacokinetics (PK) of totaltestosterone, dihydrotestosterone (DHT), and estradiol after TBS-1administration.

Population:

The population for this study is adult men 18 to 80 years of age,inclusive with fasting morning (0900 h±30 min) total serum testosterone<300 ng/dL. Subjects currently treated with testosterone must undergo 2to 4 weeks of washout depending on the route of administration.

Study Design and Duration:

This is a Phase 3, 2-group, multicenter study consisting of 4 studyperiods including 2 safety extension periods as follows:

-   -   A 3- to 7-week Screening Period that includes medication washout        for subjects currently receiving testosterone treatment;    -   A 90-day randomized, open-label Treatment Period during which        subjects will receive 5.5 mg per nostril of 4.5% TBS-1 twice        daily (BID) or three times daily (TID) with potential daily dose        adjustment on Day 45 for subjects in the BID treatment group as        determined by the serum total testosterone PK profile;    -   A 90-day open-label Safety Extension Period (Safety Extension        Period 1) for all study subjects; and    -   An additional 180-day open-label Safety Extension Period (Safety        Extension Period 2) for a subset of 75 subjects.

The approximate total duration of study participation for subjectscompleting all 4 periods will be up to 406 days (˜58 weeks).

Screening Period

The Screening Period will take place over 3 to 7 weeks and will consistof up to 3 study visits. The duration of screening will depend onwhether subjects are naïve to testosterone treatment or if they arecurrently being treated with a testosterone product. Subjects currentlybeing treated with a testosterone product will require a washout. Theduration of washout will depend on the type of testosterone therapy andthe date of their last dose. For subjects taking testosteroneinjections, there must be at least 4 weeks between their lasttestosterone injection and the first measurement of morning serum totaltestosterone for qualification. For subjects taking oral, topical, orbuccal testosterone, there must be at least 2 weeks between the lastadministration of testosterone and the first measurement of morningserum total testosterone for qualification.

Visit 1 will occur up to 7 weeks (Week—7) prior to randomization forsubjects currently receiving testosterone injections, up to 5 weeks(Week—5) prior to randomization for subjects currently receiving oral,topical, or buccal testosterone, and up to 3 weeks (Week—3) prior torandomization for naïve subjects. During Visit 1, informed consent willbe obtained and the subject's inclusion and exclusion criteria will beassessed based on medical interview, concomitant medications, physicalexamination, digital rectal examination (DRE) of the prostate, vitalsign measurements, and screening laboratory evaluations. For naïvesubjects, a fasting morning (0900 h±30 min) serum total testosteronelevel and baseline laboratory measurements will be assessed at Visit 1.

Non-naïve subjects will be instructed to discontinue all testosteronetherapies at Visit 1. After Visit 1, if it is determined that a subjectdoes not qualify for the study, the subject will be notified andinstructed to restart prior testosterone therapy.

Subjects undergoing washout from testosterone therapy will return forVisit 1.1 and will have fasting morning (0900 h±30 min) serum totaltestosterone levels and baseline laboratory measurements obtained. Forsubjects undergoing washout of testosterone injections, Visit 1.1 willoccur 4 weeks after the last testosterone injection (up to Week—3). Forsubjects undergoing washout of oral, topical, or buccal testosterone,Visit 1.1 will occur 2 weeks after the last administration oftestosterone (up to Week—3). Visit 1.1 is not required for naïvesubjects.

At Visit 2 (up to Week—2), all subjects will have a fasting morning(0900 h±30 min) serum total testosterone level and 12-leadelectrocardiogram (ECG) assessed. At the screening visits (Visits 1,1.1, and 2), serum total testosterone levels will be measured using avalidated assay developed by Medpace Reference Laboratories. The resultswill be used for determination of a subject's inclusion or exclusionfrom the study. To be included in the study, subjects must have 2fasting morning (0900 h±30 min) serum total testosterone levels <300ng/dL. In subjects with a known history of male hypogonadism, if 1 ofthe 2 serum total testosterone levels is 300 ng/dL, the serum totaltestosterone level may be retested once. After retesting, if 2 of the 3levels are <300 ng/dL, then the subject will be eligible to participatein the study.

Subjects who qualify for the study based on screening assessments atVisits 1, 1.1, and 2 will be scheduled for an otorhinolaryngological(ENT) examination with nasal endoscopy performed by an ENT specialist.All qualified subjects will also have dual-energy x-ray absorptiometryscans scheduled in the interval between Visit 2 and randomization (Visit3) for the assessment of body composition and bone mineral density.

Treatment Period

The randomized, open-label Treatment Period will consist of 4 studyvisits: Visit 3 (Day 1), Visit 4 (Day 30), Visit 5 (Day 60), and Visit 6(Day 90).

Visit 3 (Day 1) will take place in the evening. At Visit 3, subjectswill be randomized in a 3:1 ratio to 1 of the following 2 treatmentgroups:

-   -   5.5 mg per nostril of 4.5% TBS-1 BID or    -   5.5 mg per nostril of 4.5% TBS-1 TID.

Baseline levels of fasting serum total testosterone, DHT, and estradiolwill be measured. Study drug (TBS-1) will be administered at 2100 h and0700 h in the BID treatment group (total daily dose of 22 mg/day) and at2100 h, 0700 h, and 1300 h in the TID treatment group (total daily doseof 33 mg/day). The first dose of study drug will be administered atVisit 3 (Day 1) at 2100 h and training on drug administration will beprovided to subjects. Subjects will be asked to maintain a daily diarydocumenting administration of study drug doses throughout the TreatmentPeriod, Safety Extension Period 1, and Safety Extension Period 2.

At Visit 4 (Day 30 to Day 31), study drug will be administered at thesite, beginning with the 2100 h dose of TBS-1. Subjects will be requiredto remain at the site for 24 hours after the 2100 h drug administrationand complete post-dose PK profiles for serum total testosterone, DHT,and estradiol will be obtained. The 24-hour C_(avg) of serum totaltestosterone for subjects in the BID group will be estimated based onthe sum of serum total testosterone levels collected at 2 samplingpoints during the 24-hour PK profile: the sample collected at 9.0 hours(at 1 hour before the morning 0700 h dose) and the sample collected at10.33 hours (20 minutes after the morning 0700 h dose). The followingtitration criteria will be used:

-   -   If the sum of the serum total testosterone level values for PK        samples collected at 9.0 hours and 10.33 hours is <755 ng/dL,        then the estimated 24-hour C_(avg) is <300 ng/dL and    -   If the sum of the serum total testosterone level values for PK        samples collected at 9.0 hours and 10.33 hours is ≥755 ng/dL,        then the estimated 24-hour C_(avg) is ≥300 ng/dL.

Subjects randomized to the BID group with an estimated serum totaltestosterone C_(avg)<300 ng/dL, will be contacted by phone andinstructed to increase the daily dose of TBS-1 to TID on Day 45. Thedecision to increase the subject's daily dose to TID will be made by theinvestigator based on the criteria specified above. This daily dose willbe continued throughout the remainder of the Treatment Period and, asapplicable, both Safety Extension Periods.

At Visit 6 (Day 90 to Day 91), study drug will be administered at thesite, beginning with the 2100 h dose of TBS-1. Subjects will be requiredto remain at the site for 24 hours after the 2100 h drug administrationand complete post-dose PK profiles for serum total testosterone, DHT,and estradiol will be obtained.

At Visits 3, 4, and 6, serum total testosterone, DHT, and estradiollevels will be measured using a sensitive and specific assay developedand validated by Analytisch Biochemisch Laboratorium BV. The resultswill be used for PK analyses.

Safety Extension Period 1

All subjects will continue into Safety Extension Period 1 and will beinstructed to continue their current daily dose of TBS-1 for the 90-daySafety Extension Period (Day 90 to Day 180). Subjects will return to thesite for monthly visits.

Safety Extension Period 2

A subset of approximately 75 subjects will continue in the study for anadditional 180-day Safety Extension Period (Day 180 to Day 360). Thesubset of subjects who continue into Safety Extension Period 2 willconsist of the first subjects to complete Safety Extension Period 1. Forthe duration of Safety Extension Period 2, subjects will remain on thesame daily dose of TBS-1 administered on Day 90 of the Treatment Periodand throughout Safety Extension Period 1. Subjects will return to thesite for monthly visits.

Dosage Forms and Route of Administration:

Study Drug: 4.5% TBS-1 Pharmaceutical form: Gel for intranasaladministration Content: Active ingredient: testosterone Excipients:silicon dioxide, castor oil, and oleoyl polyoxylglycerides Mode ofIntranasal administration: Batch number: To be determined Storageconditions: Between 15-25° C.

TBS-1 is administered intranasally by the subject. A multiple-dosedispenser will be used for gel deposition into the nasal cavity. Thedispenser is a finger-actuated dispensing system designed to deliver 5.5mg of 4.5% TBS-1 gel per actuation from a non-pressurized container intothe nasal cavity. The dispenser is designed to administer 45 doses (90actuations) of TBS-1. The key components of the multiple-dose dispenserinclude a barrel, base, pump, and actuator, which are composed ofpolypropylene, and a piston, which is composed of polyethylene.

Efficacy Variables:

The primary efficacy variable is the number and percentage of subjectswith a serum total testosterone C_(avg) value within the normal range(≥300 ng/dL and ≤1050 ng/dL) on Day 90.

Secondary efficacy variables include the following:

-   -   The number and percentage of subjects with a serum total        testosterone maximum concentration (C_(max)) value in the        following ranges on Day 90:        -   ≤1500 ng/dL,        -   >1500 and <2500 ng/dL, and        -   ≥2500 ng/dL;    -   The number and percentage of subjects with a serum total        testosterone C_(avg) value in the normal range (≥300 ng/dL and        ≤1050 ng/dL) on Day 30;    -   The number and percentage of subjects with a serum total        testosterone C_(max) value in the following ranges on Day 30:        -   ≤1500 ng/dL,        -   >1500 and <2500 ng/dL, and        -   ≥2500 ng/dL;    -   The complete PK profile (including C_(avg), the minimum        concentration, C_(max), and time to maximum concentration) of        serum total testosterone on Day 30 and Day 90;    -   The time within the normal range for serum total testosterone        based on the PK profile on Day 30 and Day 90;    -   The PK profile of serum estradiol on Day 30 and Day 90;    -   The PK profile of serum DHT on Day 30 and Day 90;    -   The ratio of DHT C_(avg) to total testosterone C_(avg) on Day 30        and Day 90;    -   The Positive and Negative Affect Schedule scores at baseline,        Day 30, Day 60, and Day 90;    -   The International Index of Erectile Function scores at baseline,        Day 30, Day 60, and Day 90;    -   Change in bone mineral density from baseline to Day 180; and

Change in body composition (total body mass, lean body mass, fat mass,and percent fat) from baseline to Day 180.

Safety Variables:

Safety assessments will include adverse events, clinical laboratorymeasurements (chemistry profile, liver function tests, fasting lipidprofile, hematology, urinalysis, glycosylated hemoglobin, prostatespecific antigen, and endocrine profile), 12-lead ECG parameters, vitalsigns (blood pressure, heart rate, temperature, and respiratory rate),physical examination parameters, DREs of the prostate, and ENTexaminations.

Statistical Analyses:

The intent-to-treat (ITT) population will consist of all subjects whoreceive randomized study drug and have at least 1 valid post-baselineefficacy measurement. The safety population will consist of all subjectswho receive randomized study drug and have safety measurements duringthe treated periods. The efficacy analyses will be based on the ITTpopulation and the safety analyses will be based on the safetypopulation. The primary efficacy parameter, the C_(avg) of serum totaltestosterone at Day 90, will be calculated from the area under the curve(AUC) using the following formula:C _(avg)=AUC_(0-24h)/24

The AUC curve for both BID and TID dosing regimens will be determinedfor the 0 to 24-hour time interval by using the linear trapezoidal rule.

The number and percentage of subjects who reach the treatment goal (ie,serum total testosterone C_(avg) value in the normal range) at Day 90 orEarly Termination will be summarized descriptively. The analysis andcalculation for the frequency of attaining the secondary studyobjectives will be performed using similar methods.

The concentrations of serum total testosterone, DHT, and estradiol willbe provided for baseline, Day 90 or Early Termination, and the changefrom baseline to Day 90 or Early Termination.

The same summary will be performed at Day 30 for the purpose ofcomparing the treatment difference between BID and TID after 30 days oftreatment.

For other efficacy measurements, descriptive statistics will be providedat each visit. If appropriate, the change from baseline to post-baselinevisits will be determined. The descriptive summary will also be providedfor the safety extension periods.

In addition, the Day 30 24-hour C_(avg) serum total testosterone valuesfor all subjects in the BID treatment group will be compared to theestimated value determined by the titration criteria. The acceptabilityof the titration criteria will be assessed.

Adverse events will be coded using the latest version of the MedicalDictionary for Regulatory Activities. A general summary of the adverseevents and serious adverse events for each treatment group will bepresented by the overall number of adverse events, the severity, and therelationship to study drug. The incidence of adverse events will besummarized by system organ class, preferred term, and treatment group.The safety laboratory data will be summarized by visit and by treatmentgroup along with the change or percent change from baseline. Vital signswill also be summarized by visit and by treatment group along with thechange from baseline. The clinical findings in the physical examinationand 12-lead ECG results will be summarized at each scheduled visit.Other safety measurements will be summarized and listed if deemednecessary.

Sample Size Determination:

A sample size of approximately 280 subjects (210 subjects randomized tothe BID treatment group and 70 subjects randomized to the TID treatmentgroup) was selected to provide a sufficient number of subjects todetermine the efficacy, safety, and tolerability of intranasal 4.5%TBS-1 gel. Since this is an observational study, no formal sample sizecalculation was performed.

Preliminary data on 139 hypogonadal men who have completed 30 days ofBID or TID treatment of the Phase 3 Study exhibit the following results,established by in accordance with the titration methods set forth inExample 15 below and as described herein:

-   -   107 males were treated with the BID dosing regimen, 4.5% TBS-1,        and 32 males on the TID regimen    -   Approximately 80% of the males treated with 4.5% TBS-1 achieved        an average testosterone level above 300 ng/dl    -   Both the BID and TID treatment groups had more than 75% of the        patients above the average testosterone level 300 ng/dl cut-off.

In accordance with the present invention, an exemplary label is providedin Exhibit E (the contents of which are incorporated herein byreference).

Example 14 Statistical Analysis Plan A 90-Day, Randomized, Dose-RangingStudy, Including Potential Dose Titration, Evaluating the Efficacy andSafety of Intranasal TBS-1 in the Treatment of Male Hypogonadism withSequential Safety Extension Periods of 90 and 180 Days InvestigationalProduct: 4.5% TBS-1 Intranasal Testosterone Gel Protocol Number:TBS-1-2011-03

Introduction

This example provides a description of the statistical methods andprocedures to be implemented for the analyses of data from the studywith protocol number TBS-1-2011-03. See also Exhibit C (the contents ofwhich are incorporated herein by reference).

Study Design and Objectives

Study Objectives

Primary Objective

The primary objective of the study is to determine the efficacy of 4.5%TBS-1 gel, administered as 2 or 3 daily intranasal doses of 5.5 mg pernostril, as demonstrated by an increase in the 24-hour averageconcentration (C_(avg)) of serum total testosterone to the normal range(≥300 ng/dL and ≤1050 ng/dL) in 75% of male subjects treated forhypogonadism.

Secondary Objective

The secondary objectives of this study are the following:

-   -   To determine the efficacy of 4.5% TBS-1 gel, administered 2 or 3        times daily at a dose of 5.5 mg per nostril, in achieving the        following for serum total testosterone maximum concentration        (C_(max)):        -   C_(max)≤1500 ng/dL in ≥85% of subjects,        -   C_(max) 1800 to 2500 in <5% of subjects, and        -   C_(max)>2500 ng/dL in no subjects;    -   To determine the safety and tolerability of TBS-1 after 90, 180,        and 360 days of treatment;    -   To determine the effect of TBS-1 treatment on body composition        (total body mass, lean body mass, fat mass, and percent fat);    -   To determine the effect of TBS-1 treatment on bone mineral        density (lumbar spine and hip);    -   To determine the effect of TBS-1 treatment on mood;    -   To determine the effect of TBS-1 treatment on erectile function;        and    -   To determine the serum concentration and pharmacokinetics (PK)        of total testosterone, dihydrotestosterone (DHT), and estradiol        after TBS-1 administration.        Study Design and Duration

This is a Phase 3, 2-group, multicenter study consisting of 4 studyperiods including 2 safety extension periods as follows:

-   -   A 3- to 7-week Screening Period that includes medication washout        for subjects currently receiving testosterone treatment;    -   A 90-day randomized, open-label Treatment Period during which        subjects will receive 5.5 mg per nostril of 4.5% TBS-1 twice        daily (BID) or three times daily (TID) with potential daily dose        adjustment on Day 45 for subjects in the BID treatment group as        determined by the serum total testosterone PK profile;    -   A 90-day open-label Safety Extension Period (Safety Extension        Period 1) for all study subjects; and    -   An additional 180-day open-label Safety Extension Period (Safety        Extension Period 2) for a subset of 75 subjects.

The approximate total duration of study participation for subjectscompleting all 4 periods will be up to 406 days (˜58 weeks).

Screening Period

The Screening Period will take place over 3 to 7 weeks and will consistof up to 3 study visits. The duration of screening will depend onwhether subjects are naïve to testosterone treatment or if they arecurrently being treated with a testosterone product. Subjects currentlybeing treated with a testosterone product will require a washout. Theduration of washout will depend on the type of testosterone therapy andthe date of their last dose. For subjects taking testosteroneinjections, there must be at least 4 weeks between their lasttestosterone injection and the first measurement of morning serum totaltestosterone for qualification. For subjects taking oral, topical, orbuccal testosterone, there must be at least 2 weeks between the lastadministration of testosterone and the first measurement of morningserum total testosterone for qualification.

Visit 1 will occur up to 7 weeks (Week—7) prior to randomization forsubjects currently receiving testosterone injections, up to 5 weeks(Week—5) prior to randomization for subjects currently receiving oral,topical, or buccal testosterone, and up to 3 weeks (Week—3) prior torandomization for naïve subjects. During Visit 1, informed consent willbe obtained and the subject's inclusion and exclusion criteria will beassessed based on medical interview, concomitant medications, physicalexamination, digital rectal examination (DRE) of the prostate, vitalsign measurements, and screening laboratory evaluations. For naïvesubjects, a fasting morning (0900 h±30 min) serum total testosteronelevel and baseline laboratory measurements will be assessed at Visit 1.

Non-naïve subjects will be instructed to discontinue all testosteronetherapies at Visit 1. After Visit 1, if it is determined that a subjectdoes not qualify for the study, the subject will be notified andinstructed to restart prior testosterone therapy.

Subjects undergoing washout from testosterone therapy will return forVisit 1.1 and will have fasting morning (0900 h±30 min) serum totaltestosterone levels and baseline laboratory measurements obtained. Forsubjects undergoing washout of testosterone injections, Visit 1.1 willoccur 4 weeks after the last testosterone injection (up to Week—3). Forsubjects undergoing washout of oral, topical, or buccal testosterone,Visit 1.1 will occur 2 weeks after the last administration oftestosterone (up to Week—3). Visit 1.1 is not required for naïvesubjects.

At Visit 2 (up to Week—2), all subjects will have a fasting morning(0900 h±30 min) serum total testosterone level and 12-leadelectrocardiogram (ECG) assessed.

At the screening visits (Visits 1, 1.1, and 2), serum total testosteronelevels will be measured using a validated assay developed by MedpaceReference Laboratories. The results will be used for determination of asubject's inclusion or exclusion from the study. To be included in thestudy, subjects must have 2 fasting morning (0900 h±30 min) serum totaltestosterone levels <300 ng/dL.

Subjects who qualify for the study based on screening assessments atVisits 1, 1.1, and 2 will be scheduled for an otorhinolaryngological(ENT) examination with nasal endoscopy performed by an ENT specialist.All qualified subjects will also have dual-energy x-ray absorptiometryscans scheduled in the interval between Visit 2 and randomization (Visit3) for the assessment of body composition and bone mineral density.

Treatment Period

The randomized, open-label Treatment Period will consist of 4 studyvisits: Visit 3 (Day 1), Visit 4 (Day 30), Visit 5 (Day 60), and Visit 6(Day 90).

Visit 3 (Day 1) will take place in the evening. At Visit 3, subjectswill be randomized in a 3:1 ratio to 1 of the following 2 treatmentgroups:

-   -   5.5 mg per nostril of 4.5% TBS-1 BID or    -   5.5 mg per nostril of 4.5% TBS-1 TID.

Baseline levels of fasting serum total testosterone, DHT, and estradiolwill be measured. Study drug (TBS-1) will be administered at 2100 h and0700 h in the BID treatment group (total daily dose of 22 mg/day) and at2100 h, 0700 h, and 1300 h in the TID treatment group (total daily doseof 33 mg/day). The first dose of study drug will be administered atVisit 3 (Day 1) at 2100 h and training on drug administration will beprovided to subjects. Subjects will be asked to maintain a daily diarydocumenting administration of study drug doses throughout the TreatmentPeriod, Safety Extension Period 1, and Safety Extension Period 2.

At Visit 4 (Day 30 to Day 31), study drug will be administered at thesite, beginning with the 2100 h dose of TBS-1. Subjects will be requiredto remain at the site for 24 hours after the 2100 h drug administrationand complete post-dose PK profiles for serum total testosterone, DHT,and estradiol will be obtained. The 24-hour C_(avg) of serum totaltestosterone for subjects in the BID group will be estimated based onthe sum of serum total testosterone levels collected at 2 samplingpoints during the 24-hour PK profile: the sample collected at 9.0 hours(at 1 hour before the morning 0700 h dose) and the sample collected at10.33 hours (20 minutes after the morning 0700 h dose). The followingtitration criteria will be used:

-   -   If the sum of the serum total testosterone level values for PK        samples collected at 9.0 hours and 10.33 hours is <755 ng/dL,        then the estimated 24-hour C_(avg) is <300 ng/dL and    -   If the sum of the serum total testosterone level values for PK        samples collected at 9.0 hours and 10.33 hours is ≥755 ng/dL,        then the estimated 24-hour C_(avg) is ≥300 ng/dL.

Subjects randomized to the BID group with an estimated serum totaltestosterone C_(avg)<300 ng/dL, will be contacted by phone andinstructed to increase the daily dose of TBS-1 to TID on Day 45. Thedecision to increase the subject's daily dose to TID will be made by theinvestigator based on the criteria specified above. This daily dose willbe continued throughout the remainder of the Treatment Period and, asapplicable, both Safety Extension Periods.

At Visit 6 (Day 90 to Day 91), study drug will be administered at thesite, beginning with the 2100 h dose of TBS-1. Subjects will be requiredto remain at the site for 24 hours after the 2100 h drug administrationand complete post-dose PK profiles for serum total testosterone, DHT,and estradiol will be obtained.

At Visits 3, 4, and 6, serum total testosterone, DHT, and estradiollevels will be measured using a sensitive and specific assay developedand validated by Analytisch Biochemisch Laboratorium BV. The resultswill be used for PK analyses.

Safety Extension Period 1

All subjects will continue into Safety Extension Period 1 and will beinstructed to continue their current daily dose of TBS-1 for the 90-daySafety Extension Period (Day 90 to Day 180). Subjects will return to thesite for monthly visits.

Safety Extension Period 2

A subset of approximately 75 subjects will continue in the study for anadditional 180-day Safety Extension Period (Day 180 to Day 360). Thesubset of subjects who continue into Safety Extension Period 2 willconsist of the first subjects to complete Safety Extension Period 1. Forthe duration of Safety Extension Period 2, subjects will remain on thesame daily dose of TBS-1 administered on Day 90 of the Treatment Periodand throughout Safety Extension Period 1. Subjects will return to thesite for monthly visits.

A table of the schedule of procedures can be found below:

Schedule of Procedures

Study Phase Safety Screening Treatment Period Extension Safety ExtensionPrior Testosterone Rando- Period 1 Period 2^(d) Testosterone Treatmentmiza- Efficacy Safety Subset Treatment Naive tion Analysis AnalysisSafety Analysis Study Timing Day 120 Day 210 Day 300 Week-7 Day 30- Day90- and and and or -5a Week-3 Week-2 Week-3 Week-2 Day 1 Day 31^(p) Day60 Day 91^(q) Day 150 Day 180 Day 240 Day 270 Day 330 Day 360 VisitNumber Early Study Procedures 1 1.1^(b) 2 1 2 3 4^(c) 5 6 7-8^(e) 910-11^(e) 12 13-14 15 Termination Inclusion/exclusion criteria x x x x xInformed consent x x Medical interview x x Physical examination x x x xx x x Height and weight x x Vital signs (HR, BP, RR, and temperature) xx x^(r) x^(r) x x^(r) x x x x x x x Concomitant medications x x x x x xx x x x x x x x x x DRE of the prostate x x x x x x x Chemistry profileand hematology^(f) x x x x x x x x x Fasting lipid profile^(g) x x x x xx x x x Liver function tests^(h) x x x x x x x x x HbA_(1c) andendocrine profile^(i) x x x x Urinalysis^(j) x x x x x x x x Urine drugand alcohol screen x x PSA x x x x x x x Estradiol and DHT^(k) x x x x xx x x Free testosterone x x x x 12-lead electrocardiogram x x x x x x xFasting serum total testosterone^(k) x x x x x x x x x ENT exam withnasal endoscopy^(l) x x DEXA^(m) x x x x IIEF and PANAS questionnaires xx x x x^(o) Administer study drug at the site x x x 24-h PK profile forserum total testosterone, x x DHT, and estradiol Basic ENT examination(non-endoscopic) x x x x x x x x x x x Potential study drug daily dosetitration x Distribute and/or review daily diary^(n) x x x x x x^(s) x xx x Weigh study drug dispensers x x x x x x x x x x x Prime study drugdispensers and distribute to x x x x x x^(s) x x x x subjects Assessadverse events x x x x x x x x x x x x x x ^(a)Visit 1 for subjectsreceiving intramuscular testosterone injections at the time of screeningwill occur at up to Week-7. Visit 1 for subjects receiving buccal, oral,or topical testosterone will occur at up to Week-5. ^(b)Visit 1.1 isonly required for subjects who have undergone washout of testosteronetherapy and will take place 4 weeks after the last administration oftestosterone for subjects taking testosterone injections and 2 weeksafter the last testosterone administration for subjects taking buccal,oral, or topical testosterone. ^(c)Based on the PK profile for serumtotal testosterone performed at Visit 4, some subjects in the BIDtreatment group will have their daily dose increased to TID. Subjectsthat require a daily dose increase will be contacted by phone andinstructed to increase their daily dose on Day 45. ^(d)A subset ofapproximately 75 subjects will be enrolled in Safety Extension Period 2.^(e)During Safety Extension Period 1 and Safety Extension Period 2,study visits will be conducted once per month. ^(f)Chemisty profileincludes: creatine kinase, sodium, potassium, glucose, blood ureanitrogen, creatinine, calcium, phosphorus, and uric acid. Hematologyincludes: hemoglobin, hematocrit, red blood cell count, white blood cellcount and differential, platelets, reticulocyte count, mean corpuscularvolume, mean corpuscular hemoglobin, , and mean corpuscular hemoglobinconcentration. ^(g)Fasting lipid profile includes: total cholesterol,low-density lipoprotein-cholesterol (direct), high-density lipoproteincholesterol, and triglycerides. ^(h)Liver function tests include: totalbilirubin, albumin, aspartate aminotransferase, alanineaminotransferase, alkaline phosphatase, and gamma glutamyl transferase.^(i)Endocrine profile includes: thyroid-stimulating hormone, morningcortisol, sex hormone-binding globulin, luteinizing hormone,follicle-stimulating hormone, and prolactin. ^(j)Urinalysis includes:specific gravity, glucose, protein, ketones, pH, blood, bilirubin,urobilinogen, nitrite, and leukocyte esterase. ^(k)Fasting serum totaltestosterone, DHT, and estradiol should be collected at 0900 h ± 30 minat Visits 1, 1.1, 2, 9, 12, 15, and Early Termination and at 2045 h atVisit 3. In subjects with a known history of male hypogonadism, if 1 ofthe 2 serum total testosterone levels collected at screening is ≥300ng/dL, the serum total testosterone level may be retested once. Afterretesting, if 2 of the 3 levels are <300 ng/dL, then the subject will beeligible to participate in the study. ^(l)ENT examination with nasalendoscopy performed by an ENT specialist will be scheduled for theinterval between Visit 2 and Visit 3 (Day 1 [randomization]) onqualified subjects. ^(m)DEXA scans to evaluate body composition (totalbody mass, lean body mass, fat mass, and percent fat) and bone density(lumbar spine and hip) will be performed in the interval between Visit 2and Visit 3 on qualified subjects. Follow-up DEXA will be obtained atVisit 9 (Day 180) and Visit 15 (Day 360), if scheduling is available, orwithin ±2 weeks of Visit 9 and Visit 15. ^(n)Daily diary will bedistributed to subjects to record date and time of study drugadministration. ^(o)IIEF and PANAS questionnaires will be administeredto subjects at Early Termination if subjects terminate on or beforeVisit 6 (Day 90). ^(p)On Day 31 of Visit 4, the following procedureswill be performed: vital sign measurements, basic ENT examination,administer questionnaires (may be performed on Day 30 or Day 31), anddispense daily diary. ^(q)On Day 91 of Visit 6, the following procedureswill be performed: vital sign measurements, basic ENT examination,dispense daily diary, administer questionnaires (may be performed on Day90 or Day 91), perform DRE (may be performed on Day 90 or Day 91), andperform physical examination (may be performed on Day 90 or Day 91).^(r)At Visit 3 (Day 1), vital sign measurements will be obtained priorto first dose of study drug and at approximately 1 hour after the firstdose of study drug (at 2200 h). On Day 30 of Visit 4 and Day 90 of Visit6, vital sign measurements will be obtained once prior to administrationof study drug. On Day 31 of Visit 4 and Day 91 of Visit 6, vital signmeasurements will be obtained at the following approximate times afteradministration of study drug: 6 hours (at 0300 h), 12 hours (at 0900 h),18 hours (at 1500 h), and 24 hours (at 2100 h). ^(s)At Visit 9, studydrug dispensers and daily diaries will only be distributed to subjectsentering Safety Extension Period 2. BID = twice daily; BP = bloodpressure; DEXA = dual-energy x-ray absorptiometry; DRE = digital rectalexamination; DHT = dihydrotestosterone; ENT = otorhinolaryngological;HbA_(1c) = glycosylated hemoglobin; HR = heart rate; IIEF =International Index of Erectile Function; PANAS = Positive and NegativeAffect Schedule; PK = pharmacokinetic; PSA = prostate specific antigen;RR = respiratory rate; TID = three times daily.Efficacy VariablesPrimary Efficacy Variable

The primary efficacy variable is the number and percentage of subjectswith a serum total testosterone C_(avg) value within the normal range(≥300 ng/dL and ≤1050 ng/dL) on Day 90.

Secondary Efficacy Variables

Secondary efficacy variables include the following:

-   -   The number and percentage of subjects with a serum total        testosterone maximum concentration (C_(max)) value in the        following ranges on Day 90:        -   ≤1500 ng/dL,        -   ≥1800 and ≤2500 ng/dL, and        -   >2500 ng/dL;    -   The number and percentage of subjects with a serum total        testosterone C_(avg) value in the normal range (≥300 ng/dL and        ≤1050 ng/dL) on Day 30;    -   The number and percentage of subjects with a serum total        testosterone C_(max) value in the following ranges on Day 30:        -   ≤1500 ng/dL,        -   ≥1800 and ≤2500 ng/dL, and        -   >2500 ng/dL;    -   The complete PK profile (including C_(avg), the minimum        concentration, C_(max), and time to maximum concentration) of        serum total testosterone on Day 30 and Day 90;    -   The time within the normal range for serum total testosterone        based on the PK profile on Day 30 and Day 90;    -   The PK profile of serum estradiol on Day 30 and Day 90;    -   The PK profile of serum DHT on Day 30 and Day 90;    -   The ratio of DHT C_(avg) to total testosterone C_(avg) on Day 30        and Day 90;    -   The Positive and Negative Affect Schedule scores at baseline,        Day 30, Day 60, and Day 90;    -   The International Index of Erectile Function scores at baseline,        Day 30, Day 60, and Day 90;    -   Change in bone mineral density from baseline to Day 180 and from        baseline to Day 360; and    -   Change in body composition (total body mass, lean body mass, fat        mass, and percent fat) from baseline to Day 180 and from        baseline to Day 360.        Safety Variables

Safety assessments will include adverse events, clinical laboratorymeasurements (chemistry profile, liver function tests, fasting lipidprofile, hematology, urinalysis, glycosylated hemoglobin, prostatespecific antigen, and endocrine profile), 12-lead ECG parameters, vitalsigns (blood pressure, heart rate, temperature, and respiratory rate),physical examination parameters, DREs of the prostate, and ENTexaminations.

Statistical Methodology

Baseline, Endpoint, and Other Statistical Considerations

Results will be summarized by the following treatment groups:

-   -   TBS-1 BID,    -   TBS-1 BID/TID (for subjects who up-titrated at Day 45), and    -   TBS-1 TID.

For time points prior to Day 45, TBS-1 BID, TBS-1 BID/TID, and TBS-1 TIDtreatment groups will be presented even though no titration hasoccurred. Additionally, a Total TBS-1 BID treatment group (combining theTBS-1 BID and TBS-1 BID/TID groups) will be presented.

Baseline for results from the IIEF and PANAS questionnaires, vitalsigns, estradiol, DHT, and fasting serum total cholesterol will be theDay 1 value.

Baseline for body composition, bone mineral density, and 12-leadelectrocardiogram will be the Week—2 value.

Baseline for safety laboratory results will be the Week—3 value.

If the baseline value is missing, the last value prior to the first doseof study medication will be used as baseline.

Day 90 LOCF will be the Day 90 value. If missing, the last value duringthe Treatment Period will be used.

Day 180 LOCF will be the Day 180 value. If missing, the last valueduring Safety Extension Period 1 will be used.

Day 360 LOCF will be the Day 360 value. If missing, the last valueduring Safety Extension Period 2 will be used.

Descriptive statistics (n, mean, standard deviation, minimum, median,maximum) will be used to summarize the continuous efficacy and safetyvariables. For lipids and other measurements that might violate thenormal assumption, non-parametric statistics (Q1, Q3, and inter-quartilerange) will be provided in addition to the conventional parametricstatistics. The count and frequency will be used to tabulate thecategorical measurements.

Analysis Populations

Randomized Population

The randomized population will consist of all subjects who signed theinformed consent form and are assigned a randomization number at Visit 3(Day 1).

Intent-to-Treat Populations

The intent-to-treat (ITT) population for each period will consist of allsubjects who receive randomized study drug and have at least one validpost-baseline efficacy measurement in the period.

Per-Protocol Population

The per-protocol population will consist of all ITT subjects whocomplete the 90-day Treatment Period without any major protocoldeviations.

Subjects may be excluded from the per-protocol population for thefollowing reasons:

-   -   Major violations of eligibility criteria for randomization,    -   Withdrawal Prior to Day 90 or missing Day 90 PK profile,    -   Restricted concomitant medications taken during the treatment        period, or    -   Any other major protocol deviation that may interfere with the        assessment of drug efficacy.        Safety Populations

The safety population for each period will consist of all subjects whoreceive randomized study drug and have safety measurements in therespective period.

Patient Disposition

Patient disposition will be summarized by counts and percentages foreach treatment group and in total. The following categories of patientdisposition will be included:

-   -   Subjects who are randomized,    -   Subjects who complete the Treatment Period,    -   Subjects who complete the Treatment Period and Safety Extension        Period 1,    -   Subjects who enter Safety Extension Period 2, and    -   Subjects who complete Safety Extension Period 2.

For randomized subjects who discontinue from the study, the primaryreason for discontinuation will be summarized according to the period inwhich the withdrawal occurred. Reasons for discontinuation will belisted.

The total number of subjects who are screened and the total number ofscreen failures with reasons for screen failure will be tabulated.

The number and percentage of subjects in the ITT populations, PPpopulation, and safety populations will be presented by treatment groupand in total.

Demographic and Baseline Characteristics

Demographic and baseline characteristics will be summarized for allsubjects in the randomized population by treatment group and in total.

Gender, race, testosterone therapy history, smoking status, and alcoholuse will be summarized with counts and percentages. Age, height, weight,body mass index (BMI), and duration of hypogonadism will be summarizedwith descriptive statistics.

Baseline values for fasting serum total testosterone will be describedwith descriptive statistics.

Baseline is defined in Section 0

Baseline, Endpoint, and Other Statistical Considerations.

Medical history will be listed for all randomized subjects.

Prior/Concomitant Medications

Medication start and stop dates that are recorded on the Prior andConcomitant Medications Case Report Form (CRF) will be used to determinewhether the medications are prior or concomitant to the treatment andsafety extension periods. Prior medications are defined as those usedprior to and stopped before the first dose of study medication.

Concomitant medications are those that are used during the treatmentperiod or safety extension periods (i.e., start date is on or after thefirst dose date of study medication, or start prior to the date of firstdose and the stop date is either after the first dose date or marked as“continuing”).

Concomitant medication/therapy verbatim terms will be coded withAnatomical Therapeutic Chemical (ATC) class and preferred term by theWorld Health Organization

Drug Dictionary. The numbers and percentages of subjects in eachtreatment group taking concomitant medications will be summarized by ATCclass and preferred term for the safety population for the TreatmentPeriod. Concomitant medications taken during Safety Extension Period 1and Safety Extension Period 2 will be summarized in a similar manner.

Prior and concomitant medications will be listed.

Study Exposure, Dispensation, and Accountability

Days of exposure to study medication during the Treatment Period, SafetyExtension Period 1, and Safety Extension Period 2 will be summarizedwith descriptive statistics for the safety populations for eachtreatment group and overall. Contingency tables will be provided todisplay the number and percentage of subjects with exposure by visit foreach treatment group for the safety populations.

Days of exposure is defined as the date of the last dose of studymedication (in the respective period)—the date of the first dose ofstudy medication+1.

Drug dispensation and accountability data will be listed.

Analysis of Efficacy

Efficacy evaluations will be performed for the ITT populations. Theprimary efficacy analysis will be repeated for the PP population.

Analysis of the Primary Efficacy Parameter

The primary objective of this study is to determine the efficacy of 4.5%TBS-1 gel, administered intranasally BID and/or TID, in increasing theC_(avg) of serum total testosterone to the normal range (≥300 ng/dL and≤1050 ng/dL) in male subjects with hypogonadism after 90 days oftreatment. The primary efficacy parameter, C_(avg), will be calculatedfrom the AUC using the following formula:C _(avg)=AUC_(0-24h)/24.

The AUC curve for both the BID and TID dosing regimens will bedetermined for the 0-24 hour time interval by using linear trapezoidaland linear interpolation methods. Actual collection times will be usedin the calculation.

The number and percentage of subjects who reach the treatment goal (ie,serum total testosterone C_(avg) value in the normal range) at Day 90 orEarly Termination (Day 90 LOCF) will be summarized by treatment group.95% confidence intervals for the frequency will be approximated by abinomial distribution within each treatment group.

Analysis of the Secondary Efficacy Parameters

The primary efficacy analysis will be repeated for the serum totaltestosterone C_(avg) values on Day 30. Additionally, for C_(avg) on Day30, the Total BID treatment group and the TID treatment group will becompared using the chi-square test to evaluate the number of subjectswith C_(avg) within the normal range (≥300 ng/dL and ≤1050 ng/dL).

The odds ratio, 95% confidence interval, and p-value will be presented.

The serum total testosterone C_(max) values on Day 30 and Day 90 will besummarized by counts and percentages for each treatment group for thefollowing categories:

-   -   C_(max)≤1500 ng/dL,    -   1800 ng/dL≤C_(max)≤2500 ng/dL, and    -   C_(max)>2500 ng/dL.

The PK profile, including AUC_(0-24h), C_(avg), C_(min), C_(max), andT_(max), for serum total testosterone, serum estradiol, and serum DHTwill be summarized with descriptive statistics, including the arithmeticmean, standard deviation, coefficient of variation (CV %), geometricmean, median, minimum, and maximum by treatment at Day 30 and Day 90.Geometric mean and CV % will not be presented for T. The samedescriptive statistics will be calculated for serum concentrations ateach sampling time by treatment and visit.

Data will be listed individually for all subjects. A figure displayingthe distribution of the C_(avg) values at Day 30 and Day 90 will beprovided.

All concentrations below the lower limit of quantification (LLOQ) ormissing data will be labeled as such in the concentration data listings.Concentrations below the LLOQ prior to the first measurableconcentration will be treated as zero in the summary statistics and forthe calculation of PK profile parameters. Concentrations below LLOQafter the time point of the first measurable concentration will be setto missing and not included in the calculation of AUC.

The time within normal range (≥300 ng/dL and ≤1050 ng/dL) for serumtotal testosterone and the ratio of DHT C_(avg) to total testosteroneC_(avg) on Day 30 and Day 90 will be summarized with descriptivestatistics for each treatment group.

The concentrations of fasting serum total testosterone, DHT, andestradiol will be summarized with descriptive statistics at baseline,Day 30, Day 90, Day 90 LOCF, Day 180, Day 180 LOCF, Day 270, Day 360,and Day 360 LOCF. The change from baseline will also be summarized.

The change in bone mineral density, total body mass, lean body mass, fatmass, and percent fat will be summarized with descriptive statistics atbaseline, Day 180, and Day 360, as well as the change from baseline toDay 180 and the change from baseline to Day 360 for each treatmentgroup.

The Day 30 24-hour C_(avg) serum total testosterone values for allsubjects in the BID treatment group will be assessed for appropriatedose titration (from BID to TID) at Day 45.

The IIEF questionnaire will be broken up into five domains: erectilefunction, intercourse satisfaction, orgasmic function, sexual desire,and overall satisfaction. Point values will be assigned to each answerin the questionnaire according to Appendix 1. (See Appendix 1 in theAppendix to the Specification.) Domain scores will be the sum of thepoints of each question making up the domain. The breakdown can be foundin the table below.

Domain Questions Maximum Score Erectile Function 1, 2, 3, 4, 5, 15 30Intercourse 6, 7, 8 15 Satisfaction Orgasmic Function 9, 10 10 SexualDesire 11, 12 10 Overall Satisfaction 13, 14 10

The scores for each domain will be summarized with descriptivestatistics at baseline, Day 30, Day 60, Day 90, Day 90 LOCF, and thechange from baseline at each visit.

PANAS scores will be summarized with descriptive statistics for eachemotion/feeling as well as the Positive and Negative Affect Score bytreatment at baseline, Day 30, Day 60, Day 90, and Day 90 LOCF. Changefrom baseline to each visit will be provided for the Positive andNegative Affect Scores. Positive Affect Score is found by adding thescores from items 1, 3, 5, 9, 10, 12, 14, 16, 17, and 19. NegativeAffect Score is found by adding the scores from items 2, 4, 6, 7, 8, 11,13, 15, 18, and 20. A separate summary will be performed to summarizedthe PANAS scores based on how the subject ‘felt over the past week’, notincluding those scores based on how the subject ‘feels right now’.

Analysis of Safety

All analyses of safety will be conducted on the safety populations andwill be summarized by treatment group and in total. The safetyassessments include adverse events, clinical laboratory measurements,DRE of the prostate, 12-lead ECGs, vital sign measurements, basic ENTexamination, and physical examination.

Adverse Events

An adverse event (AE) is defined as any untoward medical occurrenceassociated with the use of a drug in humans, whether or not considereddrug related. An adverse event can therefore be any unfavorable and/orunintended sign (including an abnormal laboratory finding), symptom, ordisease temporally associated with the use of an investigationalmedication product, whether or not related to the investigationalmedication product. All adverse events, including observed orvolunteered problems, complaints, or symptoms, are to be recorded on theappropriate eCRF. AEs will be coded using the latest version of MedDRA.

Treatment-emergent adverse events (TEAEs) are defined as those AEs thathave a start date on or after the first dose of randomized studymedication, or occur prior to the first dose and worsen in severityduring the treatment period. Drug-related AEs are defined as those AEswith relationship to study drug as “Probable” or “Definitely Related”.

TEAEs will be summarized in which period the AE began. For example,TEAEs during Safety Extension Period 1 will be any TEAEs that occur onor after the first day of Safety Extension Period 1 through the end ofthe study or the start of Extension Period 2.

A table overview of adverse events will be provided summarizing thecounts and percentages of subjects with the following adverse eventsduring the Treatment Period:

-   -   TEAEs,    -   Maximum severity of TEAEs,    -   Drug-related TEAEs,    -   Maximum severity of drug-related TEAEs,    -   All serious adverse events (SAEs),    -   All treatment-emergent SAEs,    -   Drug-related SAEs,    -   Death due to AEs,    -   Withdrawals due to AEs, and    -   Withdrawals due to drug-related AEs.

A similar overview for TEAEs with onset date during Safety ExtensionPeriod 1 and Safety Extension Period 2 will be provided.

The counts and percentages of subjects with TEAEs during the TreatmentPeriod will be summarized for each treatment group by system organ classand preferred term. Drug-related TEAEs, SAEs, and TEAEs leading todiscontinuation of study medication during the Treatment Period will besummarized in the same manner. Summaries of maximum severity for TEAEsand drug-related TEAEs will be provided.

The counts and percentages of subjects with TEAEs during SafetyExtension Period 1 and Safety Extension Period 2 will be summarized foreach treatment group by system organ class and preferred term.Drug-related TEAEs will be summarized in the same manner.

All SAEs and TEAEs leading to discontinuation of study medication willbe listed with detailed information.

Clinical Laboratory Assessments

Continuous laboratory results for selected laboratory parameters(including hematology, chemistry, urinalysis, lipid profile, liverfunction tests, HbA_(1c) and endocrine profile) will be presented bytreatment group and summarized with descriptive statistics for eachscheduled visit and for the end of each period. The change from baselinewill also be presented.

Categorical laboratory results will be presented with the frequency andpercentage in each category by treatment group for each scheduled visitand for the end of each period.

The number and percentage of subjects with laboratory abnormalities willbe summarized by treatment group and overall for each period. The worstvalue for each subject in each period will be summarized.

Listings will be provided for all laboratory parameters.

Physical Examination, Digital Rectal Exam, ENT Exam, and Nasal Endoscopy

Physical examination findings will be summarized by treatment group withcounts and percentages for each body system for each scheduled visit andfor the end of each period. Digital rectal exam, ENT examination, andnasal endoscopy results will be summarized in a similar manner.

Physical examination, digital rectal exam, ENT exam, and nasal endoscopyfindings will be listed by subject.

Weight, BMI, Vital Signs, and 12-Lead Electrocardiogram

Weight, BMI, vital signs, and quantitative ECG parameters (Heart Rate,PR Interval, QRS Interval, and QT Interval) will be summarized withdescriptive statistics at baseline, each post-baseline visit, and theend of each period. The change from baseline will also be presented.Counts and percentages of subjects with abnormal ECG results will betabulated.

Vital signs recorded during the PK sampling and overall interpretationsfrom ECG will be listed.

Report Analyses

Two report analyses will be generated for this study.

The first analysis will be conducted after all subjects complete theTreatment Period.

The analysis will include all primary and secondary efficacy endpoints.Safety data collected through Safety Extension Period 1 will also besummarized.

After all subjects complete the study, including Safety Extension Period2, a second analysis will be generated including all safety and efficacydata.

Sample Size Determination

A sample size of approximately 280 subjects (210 subjects randomized tothe BID treatment group and 70 subjects randomized to the TID treatmentgroup) was selected to provide a sufficient number of subjects todetermine the efficacy, safety, and tolerability of 4.5% TBS-1 gel.Since this is an observational study, no formal sample size calculationwas performed.

Programming Specifications

The programming specifications, including the mock-up validity listings,analysis tables, figures, and data listings, as well as the deriveddatabase specifications, will be prepared in stand-alone documents. Theprogramming specification documents will be finalized prior to databaselock.

LIST OF ABBREVIATIONS AND DEFINITION OF TERMS

-   -   ALT Alanine transaminase    -   AST Aspartate transaminase    -   AUC Area under the curve    -   BID Twice daily    -   C_(avg) Average concentration    -   C_(max) Maximum concentration    -   C_(min) Minimum concentration    -   CRA Clinical research associate    -   CTIVRS ClinTrak™ Interactive Voice Response System    -   DEXA Dual-energy x-ray absorptiometry    -   DHEA Dehydroepiandrosterone    -   DHT Dihydrotestosterone    -   DRE Digital rectal examination    -   ECG Electrocardiogram    -   eCRF Electronic case report form    -   EDC Electronic data capture    -   ENT Otorhinolaryngological    -   FSH Follicle-stimulating hormone    -   GnRH Gonadotropin-releasing hormone    -   H2 Histamine 2    -   HbA_(1c) Glycosylated hemoglobin    -   IIEF International Index of Erectile Function    -   IRB Institutional Review Board    -   ITT Intent-to-treat    -   LH Luteinizing hormone    -   MedDRA Medical Dictionary for Regulatory Activities    -   PANAS Positive and Negative Affect Schedule    -   PDE5 Phosphodiesterase 5    -   PK Pharmacokinetic    -   PSA Prostate specific antigen    -   SAE Serious adverse event    -   SHBG Sex hormone-binding globulin    -   TID Three times daily    -   TWNR Time within the normal range    -   t_(1/2) Half-life    -   T_(max) Time to maximum concentration    -   TSH Thyroid-stimulating hormone    -   TU Testosterone undecanoate    -   ULN Upper limit of normal        See Appendix 1 in the Appendix to the Specification

Example 15 Titration Method for Dosing BID or TID IntranasalTestosterone Gels

The present invention is also concerned with a novel titration method todetermine the appropriate daily treatment regimen, i.e., a BID or TIDtreatment regimen, to administer the intranasal gels of the presentinvention to treat hypogonadism or TRT. While the preferred treatmentregimen in accordance with the present invention for administering theintranasal testosterone gels, such as 4.0% or 4.5% TBS-1 as described inExamples 1, 2, 3, 5, 7, 8, 9 and 10 above, to treat hypogonadism or TRTis twice-daily (BID) treatment regimen, the present inventioncontemplates that certain subjects may be more effectively treated witha three-times-a-day (TID) treatment regimen. Thus, the novel titrationmethod of the present invention has been developed to determine whichsubject will require a BID or TID treatment regimen to more effectivelytreat hypogonadism or TRT when treated with the intranasal testosteronegels of the present invention. See also Exhibit C (the contents of whichare incorporated herein by reference).

In carrying out the novel titration method in accordance with thepresent invention, subjects will have 2 blood draws, preferably at 7 amand at 8:20 am on the test day. The day before the first blood draw, thesubject will take at 10 pm, his evening intranasal dose of TBS-1. Ontest day, the subject will take at about 8 am, his morning intranasaldose of TBS-1.

The 24-hour C_(avg) of serum total testosterone will be estimated basedon the sum of serum total testosterone levels collected at the 2sampling points: the sample collected at about 9.0 hours (at 7 am, whichis 1 hour before the morning 0800 h intranasal dose) and the samplecollected at about 10.33 hours following the last evening's intranasaldose (20 minutes after the morning 0800 h dose+/−20 minutes). Note that,the blood draw times may be changed (+/−1 hour) but the delay betweenthe last dose and the first blood draw is preferably 9 hours+/−20minutes and the delay between the next dose administered at about 10hours+/−20 minutes after the last dose and the second blood draw ispreferably +/−20 minutes.

Testosterone serum concentrations are preferably measured by a validatedmethod at a clinical laboratory and reported in ng/dL units.

The following titration criteria is preferably used:

-   -   If the sum of the serum total testosterone level values for PK        samples collected at 9.0 hours and 10.33 hours is <755 ng/dL,        then the estimated 24-hour C_(avg) for the male patient is <300        ng/dL    -   If the sum of the serum total testosterone level values for PK        samples collected at 9.0 hours and 10.33 hours is ≥755 ng/dL,        then the estimated 24-hour C_(avg) for the male patient is ≥300        ng/dL.

With respect to those subjects with an estimated serum totaltestosterone C_(avg)<300 ng/dL, i.e., those subjects who sum of theserum total testosterone level values for PK samples collected at 9.0hours and 10.33 hours is <755 ng/dL, their BID treatment regimen shouldbe titrated to a TID treatment regimen of TBS-1 to achieve a 24-hourC_(avg) of ≥300 ng/dL. The decision to titrate the subject's daily doseto TID, however, will be made by the doctor based on the criteriaspecified above.

With respect to those subjects with an estimated serum totaltestosterone C_(avg)≥300 ng/dL, i.e., those subjects who sum of theserum total testosterone level values for pK samples collected at 9.0hours and 10.33 hours is ≥755 ng/dL, their BID treatment regimen shouldremain unchanged at a BID treatment regimen of TBS-1 since their 24-hourC_(avg) is ≥300 ng/dL. The decision to titrate the subject's daily doseto TID or remain at BID, however, will be made by the doctor based onthe criteria specified above.

It should be understood that, while it is preferred to draw blood from asubject to test the subject's serum total testosterone level values forpK samples at 9 hours and at 10.33 hours after the last evening's BIDdose, the difference in the total draw time, i.e., 10.33 hours, may varyby as much as about +/−60 minutes and preferably no more than about+/−20 minutes between one another. It should also be understood thatwhile, serum total testosterone level values for PK samples is 755 ng/dLis the preferred level to use to determine if titration to TID isnecessary, the serum total testosterone level values for PK samples mayvary as much as +/−50 and preferably no more than +/−25.

As an alternative, it should be understood that, while the titrationmethod is described above with starting the titration method based uponthe last evening's BID dose, the titration method could also be used bystarting the titration method based upon the first morning dose. Forexample, under this alternative embodiment, the first blood draw wouldbe taken at about 9 hours and the second blood draw would be taken atabout 10.33 hours after the morning dose, so long as the second blooddraw is taken at about 20 minutes after the last BID dose of the day.

Phase III Study—Rationale for the Titration Protocol for Compleo (4.5%TBS-1 Gel)

1. Introduction

At the Mar. 14, 2011 End of Phase II Meeting, the Compleo (4.5% TBS-1Gel) Phase III study includes the modifications suggested by the Agency(“FDA”) and a rationale for the choice of secondary endpoints, thetitration scheme and the ENT examination protocol. See Example ______for the final Phase 3 protocol.

The primary endpoint of this study is the percentage of subjects with aserum total testosterone C_(avg) value within the normal range on Day90. This endpoint is consistent with Agency standards used for approvalof other testosterone replacement therapy formulations. Although thereare no generally accepted lower limits of normal for serum totaltestosterone, guidelines recommend using the range of 280-300 ng/dL. Thesponsor has defined the normal range for Testosterone as 300 ng/dL to1050 ng/dL for this study. This range is consistent with Agencystandards and is in agreement with the AACF Hypogonadism and EndocrineSociety Clinical Practice Guidelines.

Secondary Endpoints

The secondary endpoints in the Compleo (4.5% TBS-1 Gel) Phase III studyand the rationale are listed below and included in the final protocol.All of the secondary endpoints proposed are well established fortestosterone replacement therapies.

DHT—

In previous trials with Compleo, following the administration ofCompleo, the DHT levels of responders were increased from below normalto within the normal range. These levels remained stable within thenormal range during the treatment and returned to basal levels afterdiscontinuation of Compleo. The upper limit of the physiologicalreference range of DHT was not achieved or exceeded by any subjects forany treatment. As DHT is the major metabolite of Testosterone, anincrease in DHT to within the normal range is evidence of Testosteronereplacement. A full DHT pharmacokinetic profile will be collected at Day30 and 90 for comparison against the baseline levels.

Body Composition and Lean Body Mass—

The effect of testosterone replacement therapy on body composition andlean body mass has been included as an additional objective measurementof efficacy. The sponsor will use DEXA to evaluate the subjects for thiscriteria at baseline and Day 90.

Bone Mineral Density—

This parameter will be measured by DEXA at baseline and Day

Erectile Function—

Erectile function was included in the proposed protocol but based on therecommendations from the Division, erectile function will now beassessed using the IIEF (International Index of Erectile FunctionQuestionnaire),

Mood Scales—

The sponsor intends to collect data on changes in subject mood comparedto baseline using the PANAS scale for information purposes only. ThePANAS scale was chosen as it is a validated instrument that measures thebalance between positive and negative mood. Data will be collected foreach subject at baseline, Day 30 and Day 90.

Study Design

The study includes a fixed dose arm for the t.i.d. administration andthe previously proposed b.i.d. titration arm. The subjects in the b.i.d.group will be evaluated at Day 30 in accordance with the establishedtitration scheme and those subjects that require titration will betitrated to t.i.d. dosing. The subjects in the b.i.d. group that are nottitrated will constitute a second fixed dose arm for b.i.d. dosing.

The sample size has been modified accordingly to ensure that sufficientsubjects are available for the safety evaluation. The new sample size of280 subjects will be split into two groups, with 210 subjects randomizedto the b.i.d. titration treatment group and 70 subjects randomized tothe t.i.d. treatment group. The sample size (see Table 1) incorporates a50% titration rate from b.i.d. to t.i.d., a 75% responder rate for allt.i.d. patients and a 20% drop out rate.

TABLE 1 Sample Size Estimation Randomization Arm b.i.d. b.i.d/t.i.d.t.i.d. Number of Subjects 210 — 70 Number Post- 105 105 70 titration(50% titration rate) Responder Rate at 100% 75% 75% Day 90 Drop Outs 20% 20% 20% Total Subjects for 84 63 42 Safety EvaluationTitration SchemeTitration Model Development

Following the discussion with the Division the recommendation toprospectively develop a titration scheme and include this in the PhaseIII study has been adopted. The titration scheme, based on twoindividual blood levels, has been designed to consistently titratesubjects from the b.i.d. treatment group to the t.i.d. treatment group,when testosterone replacement is not being achieved with b.i.d. dosing.Two hundred and ten (210) subjects will be randomized to the b.i.d.treatment group. Subjects will receive Compleo at 2100 h and 0700 h. OnDay 30, all subjects will be required to remain at the site for 24 hoursafter drug administration to obtain a 24 hour pharmacokinetic profile,actual C_(avg). Although a 24 hour profile will be taken, the fullprofile will not be used for titration decisions. A titration scheme hasbeen developed to allow for a simple and consistent assessment of eachsubject.

A number of different models were examined in the development of thetitration scheme for Compleo that included both single and multipleanalysis points. The model fit development and subsequent analysis wascompleted based on the data from the TBS-1-2010-01 study.

The model selected uses two testosterone measurements, one taken onehour prior to the morning dose (sample A, 9.00 h post 1^(st) dose) andone taken 20 minutes after the morning dose (sample B, 10.33 h (10 h20min) post 1^(st) dose). The C_(avg) for a given subject was predictedusing a ratio of the two testosterone measurements triangulated topredict the area under the curve for the morning peak. This morning peakarea was used to predict the total area under the curve for a 24 hourdosing interval which was converted to the 24 hour C_(avg) fortestosterone. This is referred to as the ‘model predicted C_(avg)’ or‘calculated C_(avg)’ in this text. The calculated C_(avg) was thencompared against the lower limit of normal of 300 ng/dL as the decisionlevel for titration. If the C_(avg) is calculated to be greater than 300ng/dL then the b.i.d. regimen is maintained. If the C_(avg) iscalculated to be less than 300 ng/dL then the patient is titrated to thet.i.d. regimen. The individual data comparing the predicted C_(avg) withthe actual C_(avg) C_(avg) is provided in Appendix 2.

The model was further challenged on simulated pharmacokinetic profiledata from 200 patients based on the 11 mg b.i.d. treatment group fromthe TBS-1-2010-01 study. Using the sampling points from the model andthe individual subject profiles from these 200 subjects, a modelpredicted C_(avg) was calculated and compared to the actual C_(avg). Theindividual data from this analysis is provided in Appendix 3. The modelwas designed to have a high degree of precision, (successful predictionrate of greater than 80%) around the decision level of 300 ng/dL, andthe data from both datasets shows a good correlation between thepredicted C_(avg) and the actual C_(avg) around this key decision level.

The titration model was used to create a titration scheme that will beutilized and challenged in the Phase III study. This scheme uses the twosampling points from the model; one sample taken one hour prior to themorning dose (Sample A) and one sample taken 20 minutes after themorning dose (Sample B). If the sum of Sample A and Sample B is 755ng/dL or greater, the 24 hour testosterone C_(avg) is predicted to begreater than 300 ng/dL and titration is not required. If the sum ofSample A and Sample B is less than 755 ng/dL, the 24 hour testosteroneC_(avg) is predicted to be lower than 300 ng/dL and titration isrequired.

Titration Model Robustness

The robustness of the model and the resulting titration scheme wasevaluated using the data from the TBS-1-2010-01 study and the 200patient simulated subject profiles. In addition to the two samplingpoints in the model, analysis was performed on three other samplingtimepoints after the morning dose, 30 minutes, 60 minutes and 90minutes. In each case the titration scheme was used to predict therequirement for titration following which each subject was sorted intoone of two groups, Titration Required or Titration Not Required. Theactual C_(avg) for each subject was used to assess the accuracy of thetitration scheme with the total number of correct and incorrecttitration predictions determined. The incorrect predictions were furtherseparated into two groups in which:

-   -   (1) Titration was not predicted but required—The titration        scheme indicated that titration was not required, whereas the        actual C_(avg) was less than 300 ng/dL. The subjects would not        be titrated.    -   (2) Titration was predicted but not required—The titration        scheme indicated that titration was required, whereas the actual        C_(avg) was greater than 300 ng/dL. The subjects would be        titrated.

The data for this analysis is shown in Table 2. The individual modeldata for each of the different sample timepoints can be found inAppendix 4, 5 and 6.

TABLE 2 Success Ratio for the Titration Model Analysis based on aComparison of Predicted and Actual 24 hour Average Concentration Values(C_(avg)) Model Dataset and Sampling Time TBS-1-2010-1 TBS-1-2010-1Simulated Simulated Data Data Sample A)-1 hr Sample A)-1 hr TBS-1-2010-1TBS-1-2010-1 TBS-1-2010-01 before AM before AM Simulated Data SimulatedData Sample A)-1 hr dosing dosing Sample A)-1 hr Sample A)-1 hr beforeAM dosing Sample B) + 20 Sample B) + 40 before AM dosing before AMdosing Sample B) + 20 min min after AM min after AM Sample B) + 60 mmSample B) + 90 min Success Criteria after AM dose dose dose after AMdose after AM dose Number of 22 200 200 200 200 Subjects Evaluated TotalCorrect (%) 18 (81.8%) 169 (84.5%) 165 (82.5%) 144 (72.5%) 147 (73.5%)Titration 3 36 37 38 43 Required 15 133 128 106 104 Not TitratedTitration predicted  4 (18.2%)  23 (11.5%)  26 (13.0%)  44 (22.0%)  50(25.0%) but not required (%) Titration not 0 (0.0%) 8 (4%)  9 (4.5%)  7(3.5%)  3 (1.5%) predicted but required (%)

As the data indicates the model is capable of predicting the need fortitration on a consistent basis with an over 80% success ratio forcorrect predictions at the proposed sampling points. This holds true forthe sampling point at 40 minutes after the morning dose as well. Atsampling points 60 minutes and 90 minutes after the morning dose theprediction success falls below 80%, which is likely explained by thevariability of the values in testosterone concentration at thesetimepoints and the added variability introduced by the simulationanalysis. The model performs slightly better using the 90 minutesampling point than the 60 minute sampling point.

accurately identify those subjects that would benefit from titrationfrom the b.i.d. to the t.i.d. dosing regimen and, in doing so, kept thenumber of subjects for which titration was not predicted but required toa minimum. The titration scheme achieved this with very low numbers ofsubjects from the TBS-1-2010-01 study data and TBS-1-2010-01 simulationdata across all post dose timepoints.

The remaining subjects that were not correctly predicted by thetitration scheme were titrated when it was not necessarily required.Based on the safety and pharmacokinetic profile data from theTBS-1-2010-01 study, none of the subjects that were on a t.i.d. regimenof 4.5% gel (33.75 mg/day) showed any supra-physiologic levels fortestosterone or high Cmax values, meaning there is no safety concernwith subjects who are titrated to t.i.d. when they were achievingacceptable testosterone levels on b.i.d. treatment.

Titration Scheme Validation

By including the titration scheme in the Phase III study and correlatingthe titration decision made with the actual measured C_(avg) on Day 30for each subject in the b.i.d. group at the end of the study, theexercise performed above on the simulation data will be repeated toevaluate and assess the accuracy of the titration. This internalvalidation will serve to support the validation scheme as proposed orprovide the necessary information required to make any modifications forthe product label.

ENT Evaluation During Safety Assessment

The detailed synopsis has been updated to clarify the procedure andcriteria for the ENT evaluation that will be included in the safetyextension for the Phase III study. As previously agreed, a long-termsafety assessment will be performed; 200 subjects will be exposed for anaddition 3 months and 50 subjects will be exposed for an additional 6months.

The purpose of the ENT examination is to determine if there have beenany adverse reactions related to the nasal cavity that were caused byeither the study drug or the multiple dose dispenser. A trainedphysician will perform the ENT examination as described.

1. History:

The examining physician will inquire about the following symptoms:

-   -   Excessive nasal dryness,    -   Excessive nasal crusting,    -   Unexpected nasal bleeding,    -   Progressive nasal pain,    -   Progressive nasal obstruction, and    -   Alternation to sense of smell.

2. Physical exam:

-   -   Using an anterior rhinoscope with a headlight or other light        source, the trained physician will look for the following:        -   Large amounts of nasal crusting,        -   Scar tissue blocking the nose,        -   Dried or fresh nasal blood, and        -   Fissuring of the nasal skin.

The safety evaluation measures (Day 90 to 180) will consist of monthlyENT examinations, vital signs and adverse events assessments. On Day 180(or early termination), subjects will also undergo a physicalexamination, 12-lead ECG, DRE of the prostate, and laboratoryassessments (CBC, PSA, chemistry profile, liver function tests, lipidprofile, urinalysis, fasting morning serum total testosterone, DHT, andestradiol).

A subset of subjects will be asked to continue in the study for a safetyextension period (Day 180 to 360). In this period, safety evaluationswill consist of monthly ENT examinations, vital signs, and adverseevents. On Day 270 and Day 360 (or early termination), subjects willalso undergo a physical examination, 12-lead ECG, DRE of the prostate,and laboratory assessments (CBC, PSA, chemistry profile, liver functiontests, lipid profile, urinalysis, fasting morning serum totaltestosterone, DHT, and estradiol).

Titration Model Results-TBS-1-2010-01 Data Testosterone Model ActualConcentration (ng/dL) Predicted 24 h Subject Time From Morning Dose 24 hCavg Cavg Number −1 hr +20 min (ng/dL) (ng/dL) C1 399 600 428 518 C2 251327 248 360 C3 344 604 406 387 C4 463 648 476 429 C5 292 558 364 410 C6161 304 199 179 C7 316 1140 624 489 A1 284 482 328 372 A2 249 363 262308 A3 303 611 392 337 A4 216 549 328 325 AS 552 872 610 523 A6 320 671425 603 A7 347 979 568 582 A8 185 424 261 248 B1 308 847 495 369 B2 3331100 614 446 B3 226 492 308 311 B4 249 658 389 351 B5 195 472 286 295 B6446 959 602 723 B7 355 370 311 359

Titration Model Results TBS-1-2010 Patient Simulation Data TestosteroneSample A taken 1 hour before the morning dose Testosterone Sample Btaken 20 minutes after the morning dose Testosterone Concentration Model(ng/dL) Predicted Actual Subject Time From Morning Dose 24 h Cavg 24 hCavg Number −1 hr +20 min (ng/dL) (ng/dL) 1 217 879 433 501 2 286 724399 393 3 406 296 278 358 4 449 665 440 392 5 367 561 367 514 6 254 566324 334 7 406 832 489 584 8 483 639 444 450 9 108 339 177 175 10 260 827430 366 11 327 550 347 322 12 522 1430 772 757 13 240 995 488 442 14 278852 447 288 15 249 448 276 330 16 523 930 574 506 17 497 726 483 423 18375 945 522 412 19 132 278 162 291 20 231 439 265 306 21 363 844 477 50522 535 770 516 505 23 340 680 403 673 24 252 630 349 346 25 231 583 322322 26 156 430 232 362 27 226 719 374 375 28 197 485 270 339 29 466 635435 459 30 232 920 455 316 31 263 897 459 431 32 183 1260 570 352 33 491655 453 436 34 277 497 306 475 35 362 403 302 441 36 140 395 212 233 37164 410 227 301 38 195 374 225 209 39 381 904 508 527 40 206 464 265 31641 176 809 389 397 42 200 485 271 282 43 479 2640 1233 877 44 280 511313 332 45 212 705 363 315 46 246 436 270 300 47 117 358 188 203 48 420679 434 308 49 262 781 412 406 50 191 688 347 359 51 381 447 327 439 52321 553 346 422 53 195 424 245 397 54 325 425 296 301 55 413 895 517 47256 179 952 447 328 57 180 472 258 249 58 206 689 354 359 59 255 563 323318 60 380 683 420 437 61 226 358 231 317 62 370 628 395 388 63 265 885455 388 64 163 475 252 245 65 302 756 418 595 66 274 597 344 377 67 250666 362 456 68 383 789 463 456 69 291 662 377 411 70 430 1060 589 417 71236 514 296 307 72 248 550 315 248 73 244 692 370 374 74 362 711 424 57275 310 1370 664 589 76 467 475 372 367 77 256 465 285 236 78 222 557 308267 79 198 727 366 333 80 371 397 304 346 81 213 993 477 549 82 288 646369 386 83 221 538 300 314 84 226 574 316 355 85 168 679 335 286 86 139507 255 334 87 211 611 325 363 88 225 686 360 412 89 265 456 285 313 90520 1140 656 510 91 207 1120 525 365 92 191 515 279 304 93 242 689 368399 94 121 916 410 331 95 105 398 199 294 96 299 686 389 348 97 153 466245 441 98 242 417 261 260 99 288 697 389 448 100 530 720 494 494 101178 685 341 211 102 410 424 330 343 103 491 646 449 401 104 443 830 503408 105 218 489 279 314 106 322 526 335 347 107 404 660 421 420 108 217491 280 281 109 277 454 289 294 110 200 281 190 229 111 258 425 270 276112 523 642 461 440 113 283 568 336 408 114 260 596 338 242 115 231 600329 389 116 481 757 489 405 117 293 543 330 370 118 261 375 251 311 119152 226 149 227 120 291 412 278 282 121 383 547 368 440 122 295 352 256295 123 276 527 317 304 124 113 1100 480 311 125 245 421 263 307 126 421666 430 499 127 313 514 327 371 128 238 787 405 432 129 256 493 296 380130 175 278 179 278 131 199 394 234 303 132 296 491 311 363 133 319 879474 342 134 274 812 429 346 135 140 412 218 220 136 466 441 359 434 137449 2330 1099 739 138 252 347 237 282 139 330 698 406 440 140 165 513268 215 141 292 667 379 389 142 306 574 348 473 143 345 319 263 292 144359 880 490 492 145 399 561 380 449 146 593 932 603 696 147 581 712 511426 148 222 356 229 229 149 231 640 344 301 150 274 1160 567 460 151 178764 372 411 152 176 1030 477 312 153 346 542 351 491 154 221 378 237 259155 236 527 302 361 156 257 456 282 358 157 146 609 298 295 158 241 358237 304 159 199 636 330 434 160 280 1220 593 506 161 370 500 344 417 162148 710 339 250 163 246 402 256 284 164 263 930 472 349 165 178 537 283275 166 393 715 438 432 167 193 426 245 246 168 148 449 236 214 169 120596 283 217 170 262 593 338 307 171 369 652 404 366 172 394 666 419 415173 289 543 329 396 174 282 548 328 329 175 225 654 347 336 176 255 970484 544 177 212 548 300 344 178 203 251 179 201 179 488 612 435 560 180247 809 417 425 181 206 565 305 280 182 134 497 249 252 183 401 442 333368 184 253 550 317 329 185 252 843 433 352 186 314 677 392 494 187 370532 357 378 188 368 551 363 342 189 241 511 297 251 190 229 794 404 379191 333 636 383 526 192 217 834 415 360 193 264 411 267 263 194 382 1180618 479 195 283 380 262 344 196 332 1360 669 442 197 310 911 483 321 198194 610 318 327 199 172 465 252 192 200 335 894 486 473See FIG. 40 ,

Titration Model Results TBS-1-2010 Patient Simulation Data TestosteroneSample A taken 1 hour before the morning dose Testosterone Sample Btaken 40 minutes after the morning dose Testosterone Model Concentration(ng/dL) Predicted Actual Subject Time From Morning Dose 24 h Cavg 24 hCavg Number −1 hr +40 min (ng/dL) (ng/dL) 1 217 1070 509 501 2 286 962493 393 3 406 399 318 358 4 449 676 445 392 5 367 1420 706 514 6 254 863441 334 7 406 991 552 584 8 483 758 490 450 9 108 229 133 175 10 260 441277 366 11 327 432 300 322 12 522 1160 665 757 13 240 565 318 442 14 278417 275 288 15 249 474 286 330 16 523 1020 610 506 17 497 992 588 423 18375 1130 595 412 19 132 379 202 291 20 231 439 256 306 21 363 858 483505 22 535 770 476 505 23 340 630 383 673 24 252 630 366 346 25 231 1130538 322 26 156 736 353 362 27 226 456 270 375 28 197 324 206 339 29 466467 369 459 30 232 348 229 316 31 263 1170 566 431 32 183 603 311 352 33491 660 455 436 34 277 426 278 475 35 362 334 275 441 36 140 485 247 23337 164 568 289 301 38 195 374 225 209 39 381 1020 554 527 40 206 410 243316 41 176 588 302 397 42 200 651 336 282 43 479 1750 881 877 44 280 686382 332 45 212 524 291 315 46 246 353 237 300 47 117 532 256 203 48 420437 339 308 49 262 988 494 406 50 191 536 287 359 51 381 770 455 439 52321 591 360 422 53 195 789 389 397 54 325 499 326 301 55 413 702 441 47256 179 786 381 328 57 180 357 212 249 58 206 662 343 359 59 255 414 264318 60 380 698 426 437 61 226 465 273 317 62 370 462 329 388 63 265 874450 388 64 163 279 175 245 65 302 1140 570 595 66 274 615 351 377 67 250830 427 456 68 383 842 484 456 69 291 848 450 411 70 430 579 399 417 71236 874 439 307 72 248 400 256 248 73 244 460 278 374 74 362 481 333 57275 310 676 390 589 76 467 589 417 367 77 256 462 284 236 78 222 462 270267 79 198 663 340 333 80 371 442 321 346 81 213 740 377 549 82 288 548330 386 83 221 454 267 314 84 226 742 383 355 85 168 626 314 286 86 139670 320 334 87 211 811 404 363 88 225 662 351 412 89 265 679 373 313 90520 681 475 510 91 207 723 368 365 92 191 691 349 304 93 242 431 266 39994 121 861 388 331 95 105 647 297 294 96 299 663 380 348 97 153 1040 471441 98 242 336 228 260 99 288 396 270 448 100 530 798 525 494 101 178494 266 211 102 410 758 462 343 103 491 646 387 401 104 443 603 413 408105 218 742 379 314 106 322 496 323 347 107 404 897 514 420 108 217 659346 281 109 277 563 332 294 110 200 438 252 229 111 258 495 298 276 112523 829 534 440 113 283 486 304 408 114 260 444 278 242 115 231 750 388389 116 481 609 431 405 117 293 969 499 370 118 261 375 282 311 119 152335 192 227 120 291 302 234 282 121 383 629 400 440 122 295 640 370 295123 276 440 283 304 124 113 1050 460 311 125 245 659 357 307 126 421 629415 499 127 313 533 334 371 128 238 513 297 432 129 256 488 294 380 130175 617 313 278 131 199 390 233 303 132 296 458 298 363 133 319 675 393342 134 274 812 440 346 135 140 286 168 220 136 466 862 525 434 137 4491530 782 739 138 252 489 293 282 139 330 421 297 440 140 165 313 189 215141 292 609 356 389 142 306 688 393 473 143 345 403 296 292 144 359 880466 492 145 399 506 358 449 146 593 1040 645 696 147 581 619 474 426 148222 273 196 229 149 231 814 413 301 150 274 1360 646 460 151 178 1300584 411 152 176 750 366 312 153 346 904 494 491 154 221 488 280 259 155236 772 398 361 156 257 538 314 358 157 146 428 227 295 158 241 437 268304 159 199 568 303 434 160 280 1530 715 506 161 370 476 334 417 162 148628 307 250 163 246 700 374 284 164 263 602 342 349 165 178 674 337 275166 393 712 437 432 167 193 437 249 246 168 148 397 215 214 169 120 596290 217 170 262 573 330 307 171 369 647 402 366 172 394 431 326 415 173289 949 489 396 174 282 461 294 329 175 225 785 399 336 176 255 1010 500544 177 212 646 339 344 178 203 386 233 201 179 488 853 530 560 180 247680 366 425 181 206 532 292 280 182 134 497 427 252 183 401 607 398 368184 253 640 353 329 185 252 716 383 352 186 314 846 458 494 187 370 552364 378 188 368 616 389 342 189 241 465 279 251 190 229 645 345 379 191333 636 387 526 192 217 834 258 360 193 264 231 196 263 194 382 649 407479 195 283 608 352 344 196 332 730 420 442 197 310 536 334 321 198 194684 347 327 199 172 285 181 192 200 335 655 391 473See FIG. 41 .

Titration Model Results TBS-1-2010 Patient Simulation Data TestosteroneSample A taken 1 hour before the morning dose Testosterone Sample Btaken 60 minutes after the morning dose Testosterone Model Concentration(ng/dL) Predicted Actual Subject Time From Morning Dose 24 h Cavg 24 hCavg Number −1 hr +60 min (ng/dL) (ng/dL) 1 217 1400 225 501 2 286 896238 393 3 406 372 315 358 4 449 822 324 392 5 367 970 262 514 6 254 554178 334 7 406 846 312 584 8 483 684 395 450 9 108 212 103 175 10 260 739212 366 11 327 373 287 322 12 522 1030 546 757 13 240 862 201 442 14 278444 379 294 15 249 298 200 330 16 523 367 461 506 17 497 615 352 423 18375 907 307 412 19 132 491 140 291 20 231 415 176 306 21 363 822 258 50522 535 917 370 505 23 340 859 392 673 24 252 735 199 346 25 231 486 210322 26 156 856 163 362 27 226 611 186 375 28 197 505 269 339 29 466 450384 459 30 232 377 220 316 31 263 693 368 431 32 183 791 216 352 33 4911020 339 436 34 277 762 199 475 35 362 371 320 441 36 140 543 117 233 37164 502 174 301 38 195 303 184 209 39 381 1000 334 527 40 206 557 209316 41 176 570 183 397 42 200 631 128 282 43 479 1040 385 877 44 280 466260 332 45 212 229 220 315 46 246 482 188 300 47 117 286 116 203 48 420386 255 308 49 262 830 220 406 50 191 601 233 359 51 381 405 337 439 52321 420 263 422 53 195 677 129 397 54 325 364 282 301 55 413 697 315 47256 179 1390 123 328 57 180 307 156 249 58 206 482 191 359 59 255 491 195318 60 380 680 341 437 61 226 463 239 317 62 370 573 299 388 63 265 819265 388 64 163 413 134 245 65 302 1110 246 595 66 274 409 236 377 67 250609 191 456 68 383 643 314 456 69 291 548 227 411 70 430 966 298 417 71236 497 185 307 72 248 486 169 248 73 244 665 183 374 74 362 605 318 57275 310 571 313 589 76 467 488 308 367 77 256 462 190 236 78 222 277 176267 79 198 459 168 333 80 371 424 229 346 81 213 1020 233 549 82 288 662247 386 83 221 373 168 314 84 226 522 243 355 85 168 768 143 286 86 139842 187 334 87 211 491 235 363 88 225 777 200 412 89 265 480 184 313 90520 757 488 510 91 207 642 193 365 92 191 673 164 304 93 242 661 211 39994 121 491 168 331 95 105 541 111 294 96 299 718 235 348 97 153 894 179441 98 242 509 184 260 99 288 541 263 448 100 530 921 362 494 101 178258 153 211 102 410 538 270 343 103 491 499 304 401 104 443 665 382 408105 218 483 198 314 106 322 534 285 347 107 404 521 307 420 108 217 402198 281 109 277 372 209 294 110 200 392 173 229 111 258 523 193 276 112523 804 438 440 113 283 899 247 408 114 260 476 176 242 115 231 486 178389 116 481 903 361 405 117 293 453 295 370 118 261 416 201 311 119 152276 140 227 120 291 409 240 282 121 383 547 284 440 122 295 536 173 295123 276 312 259 304 124 113 865 146 311 125 245 578 191 307 126 421 476313 499 127 313 545 220 371 128 238 772 190 432 129 256 393 200 380 130175 437 216 278 131 199 404 170 303 132 296 545 303 363 133 319 465 204342 134 274 917 200 346 135 140 287 124 220 136 466 794 333 434 137 4491030 292 739 138 252 347 176 282 139 330 445 321 440 140 165 271 144 215141 292 460 268 389 142 306 637 217 473 143 345 419 253 292 144 359 852327 492 145 399 690 292 449 146 593 1770 450 696 147 581 601 380 426 148222 262 213 229 149 231 290 186 301 150 274 580 195 460 151 178 871 116411 152 176 643 158 312 153 346 815 268 491 154 221 815 209 259 155 236500 203 361 156 257 498 296 358 157 146 385 162 295 158 241 344 240 304159 199 609 221 434 160 280 976 223 506 161 370 306 386 417 162 148 425181 250 163 246 487 206 284 164 263 699 222 349 165 178 346 151 275 166393 645 354 432 167 193 459 201 246 168 148 359 124 214 169 120 352 121217 170 262 398 180 307 171 369 613 305 366 172 394 518 271 415 173 289780 186 396 174 282 481 181 329 175 225 691 216 336 176 255 1190 278 544177 212 466 229 344 178 203 209 150 201 179 488 367 375 560 180 247 501208 425 181 206 483 152 280 182 134 455 99 252 183 401 605 283 368 184253 352 199 329 185 252 470 181 352 186 314 721 287 494 187 370 789 281378 188 368 277 255 342 189 241 522 182 251 190 229 711 175 379 191 333645 326 526 192 217 387 181 360 193 264 472 198 263 194 382 401 421 479195 283 726 191 344 196 332 582 305 442 197 310 534 252 321 198 194 726200 327 199 172 286 184 192 200 335 322 363 473See FIG. 42 .

Titration Model Results TBS-1-2010 Patient Simulation Data TestosteroneSample A taken 1 hour before the morning dose Testosterone Sample Btaken 90 minutes after the morning dose Testosterone Concentration Model(ng/dL) Predicted Actual Subject Time From Morning Dose 24 h Cavg 24 hCavg Number −1 hr +90 min (ng/dL) (ng/dL) 1 217 860 726 501 2 286 633531 393 3 406 407 349 358 4 449 276 571 392 5 367 949 600 514 6 254 846363 334 7 406 1360 562 584 8 483 668 524 450 9 108 274 144 175 10 260565 449 366 11 327 259 314 322 12 522 602 697 757 13 240 651 495 442 14278 361 324 288 15 249 363 246 330 16 523 614 400 506 17 497 660 499 42318 375 638 576 412 19 132 672 280 291 20 231 384 290 306 21 363 796 532505 22 535 869 652 505 23 340 763 538 673 24 252 462 443 346 25 231 250322 322 26 156 624 454 362 27 226 745 376 375 28 197 237 315 339 29 466910 411 459 30 232 343 273 316 31 263 704 429 431 32 183 420 437 352 33491 775 678 436 34 277 1610 466 475 35 362 714 329 441 36 140 212 307233 37 164 322 299 301 38 195 325 224 209 39 381 1030 620 527 40 206 387343 316 41 176 766 335 397 42 200 271 373 282 43 479 1500 682 877 44 280537 335 332 45 212 361 198 315 46 246 342 327 300 47 117 246 181 203 48420 416 362 308 49 262 812 490 406 50 191 415 356 359 51 381 880 353 43952 321 755 333 422 53 195 917 392 397 54 325 375 309 301 55 413 472 498472 56 179 907 704 328 57 180 269 219 249 58 206 490 309 359 59 255 413335 318 60 380 555 476 437 61 226 494 309 317 62 370 385 423 388 63 265627 409 388 64 163 228 259 245 65 302 709 634 595 66 274 550 307 377 67250 477 386 456 68 383 635 461 456 69 291 666 377 411 70 430 636 627 41771 236 561 329 307 72 248 345 330 248 73 244 554 408 374 74 362 443 434572 75 310 762 396 589 76 467 317 429 367 77 256 368 322 236 78 222 417224 267 79 198 585 295 333 80 371 402 357 346 81 213 917 554 549 82 288426 427 386 83 221 702 267 314 84 226 747 336 355 85 168 455 420 286 86139 622 440 334 87 211 401 315 363 88 225 658 450 412 89 265 378 334 31390 520 653 573 510 91 207 525 381 365 92 191 472 388 304 93 242 694 405399 94 121 605 275 331 95 105 437 290 294 96 299 359 457 348 97 153 504470 441 98 242 363 337 260 99 288 281 372 448 100 530 593 651 494 101178 378 196 211 102 410 286 426 343 103 491 530 444 401 104 443 634 497408 105 218 454 315 314 106 322 390 384 347 107 404 680 415 420 108 217309 278 281 109 277 319 291 294 110 200 538 266 229 111 258 342 351 276112 523 774 596 440 113 283 715 531 408 114 260 612 330 242 115 231 468322 389 116 481 394 621 405 117 293 431 335 370 118 261 358 304 311 119152 355 192 227 120 291 448 314 282 121 383 673 418 440 122 295 310 373295 123 276 368 264 304 124 113 494 439 311 125 245 444 370 307 126 421524 403 499 127 313 626 385 371 128 238 952 453 432 129 256 499 291 380130 175 344 275 278 131 199 472 271 303 132 296 301 378 363 133 319 522352 342 134 274 464 535 346 135 140 626 192 220 136 466 531 566 434 137449 1200 664 739 138 252 424 337 282 139 330 304 348 440 140 165 252 196215 141 292 362 338 389 142 306 909 423 473 143 345 269 343 292 144 359527 544 492 145 399 743 489 449 146 593 1080 1061 696 147 581 448 531426 148 222 416 217 229 149 231 523 234 301 150 274 551 383 460 151 1781150 471 411 152 176 775 368 312 153 346 667 521 491 154 221 265 340 259155 236 771 330 361 156 257 558 339 358 157 146 309 238 295 158 241 341263 304 159 199 528 363 434 160 280 916 564 506 161 370 487 304 417 162148 380 257 250 163 246 413 329 284 164 263 510 432 349 165 178 421 235275 166 393 770 466 432 167 193 475 293 246 168 148 262 228 214 169 120368 212 217 170 262 616 296 307 171 369 606 441 366 172 394 598 409 415173 289 475 480 396 174 282 427 343 329 175 225 524 411 336 176 255 864649 544 177 212 531 304 344 178 203 253 185 201 179 488 516 384 560 180247 546 336 425 181 206 396 309 280 182 134 468 264 252 183 401 663 452368 184 253 282 272 329 185 252 584 324 352 186 314 750 465 494 187 370425 520 378 188 368 392 290 342 189 241 234 343 251 190 229 390 422 379191 333 695 439 526 192 217 695 271 360 193 264 321 330 263 194 382 564352 479 195 283 630 453 344 196 332 531 410 442 197 310 323 379 321 198194 454 413 327 199 172 290 206 192 200 335 533 295 473See FIG. 43 .

Example 15 A Randomized 3-Way Cross Over Study to Assess the RelativeBioavailability, Safety and Tolerability of TBS-1 (4.5%) whenAdministered to Male Subjects with Seasonal Allergic Rhinitis inSymptomatic, Symptomatic but Treated (Oxymetazoline) and AsymptomaticStates Using an Environmental Challenge Chamber (ECC) Model

-   -   Study Title: A randomized 3-way cross over study to assess the        relative bioavailability, safety and tolerability of TBS-1        (4.5%) when administered to male subjects with seasonal allergic        rhinitis in symptomatic, symptomatic but treated (oxymetazoline)        and asymptomatic states using an environmental challenge chamber        (ECC) model    -   Investigational Intranasal Testosterone Gel (TBS-1)    -   Products: Oxmetazoline Nasal Spray (0.05%) Dactylus gemerata        pollen (challenge substance)    -   EudraCT No.: 2011-006098-24    -   Development Phase: I (Extrinsic Factor Study)        Synopsis        Study Title:        Objectives:        Primary:

The primary objective of this study was to determine and compare thepharmacokinetic (PK) profile of 11 mg TBS-1 (4.5%) administeredintranasally 3 times a day in subjects who suffered from seasonalallergic rhinitis, whilst they were in the symptomatic, symptomatic buttreated (with oxymetazoline) and asymptomatic states.

Secondary:

The secondary objective of this study was to determine and compare thelocal and systemic safety and tolerability, following 3 administrationsof TBS-1 in subjects with seasonal allergic rhinitis, whilst they werein the above states.

Methodology:

This study was an open-label, balanced, randomized 3-way crossover,three-group, three-treatment, three-period pharmacokinetic study.Otherwise healthy male human subjects within the age range of 18 to 45years with seasonal allergic rhinitis in an asymptomatic state wererandomized to 1 of 3 sequence groups (A, B and C). Subjects in sequencegroup A received treatment 1 in period I, treatment 2 in period II andtreatment 3 in period III. Subjects in sequence group B receivedtreatment 2 in period I and treatment 3 in period II and treatment 1 inperiod III. Subjects in sequence group C received treatment 3 in periodI, treatment 1 in period II and treatment 2 in period III. Subjectsrandomized to Treatment 1 (asymptomatic state) entered the ECC and wereexposed to Dactylis glomerate pollen prior to each administration ofTBS-1. Treatment 2 was administered to subjects who were in thesymptomatic state of their diagnosed seasonal allergic rhinitis and weretreated with oxymetazoline 30 min prior to the 07:00 h dose of TBS-1 and12 hours ater the first administration. Subjects were exposed toDactylis glomerate pollen in the ECC prior to each TBS-1 administration.Subjects receiving Treatment 3 were to be in the asymptomatic state (<3for TNSS and <2 for the congestion score) and received three doses ofTBS-1.

NUMBER OF SUBJECTS: Planned Sample Size: 18 Actual Sample Size: SafetySet: 18 Full PK population: 18 PK population for bioequivalence: 14Name of Finished Product:

TBS-1

Name of Active Ingredient:

Testosterone 4.5% (TBS-1)

Diagnosis and Main Inclusion Criteria:

Diagnosis: otherwise healthy male human subjects with seasonal allergicrhinitis in asymptomatic state

Main Inclusion Criteria:

-   -   1. Otherwise healthy male human subjects within the age range of        18 to 45 years inclusive with seasonal allergic rhinitis in        asymptomatic state, which was defined by a positive case history        and a positive skin prick and/or intradermal test for Dactylis        glomerata pollen allergen within 12 months of screening.    -   1. Total Nasal Symptom Score (TNSS) of ≥6/12 and a congestion        score of ≥⅔ on at least one card during the 2-hour screening        challenge.    -   2. Willingness to provide written informed consent to        participate in the study.    -   3. Body-mass index of 30 kg/m².    -   4. Absence of significant disease or clinically significant (cs)        abnormal laboratory values on laboratory evaluations, medical        history or physical examination during screening.    -   5. Otorhinolaryngological examination without clinically        significant abnormal findings within 4 weeks of screening.    -   6. Non-smokers or ex-smokers for at least six months.

Comprehension of the nature and purpose of the study and compliance withthe requirement of the protocol.

STUDY DRUGS, DOSE AND MODE OF ADMINISTRATION, BATCH NUMBER: Study drug:Intranasal testosterone gel (TBS-1) Form and description: Multiple-dosedispenser Unit strength: 5.5 mg of 4.5% testosterone gel Daily dose:33.0 mg of 4.5% testosterone gel Route of administration: intranasalPosology: t.i.d. Batch number: 2372 Oxymetazoline (Nasivin ® ohne Studydrug: Konservierungsstoffe) Form and description: Multiple-dosedispenser Unit strength: 0.05% oxymetazoline hydrochloride Daily dose: 4puffs (2 per nostril) of 5.05% oxymetazoline hydrochloride Route ofadministration: Intranasal Posology: 30 min prior to the 07:00 h dose ofTBS-1 and 12 h after the first dose (during Treatment Sequence 3) Studydrug: Dactylis glomerata (pollen) Form and description: Challengesubstance for pollen chamber Unit strength: 6 g Daily dose: 4000 ± 500of Dactylis glomerate pollen Route of administration: Inhalation STUDYPERIOD: 5 weeksCriteria for Evaluation:Primary Endpoint (Pharmakokinetics):

The following pharmacokinetic (PK) parameters were determined for allsubjects in all treatments: Area under the serum concentration time plotup to 24 h (AUC₀₋₂₄), the average of the observed concentration oftestosterone and DHT in the 24 h interval (C_(avg)), minimum observedconcentration of testosterone and DHT (C_(min)), maximum observedconcentration of testosterone and DHT (C_(max)), and time of maximumobserved concentration testosterone and DHT (t_(max)) for 3 treatmentphases (Treatments 1-3). The relative PK profiles of the 3 treatmentswere determined using AUC₀₋₂₄ and C_(max) corrected for the serumtestosterone concentration.

Secondary Endpoint (Safety):

Safety and tolerability were assessed by monitoring:

-   -   Adverse events    -   Otolaryngological examination    -   Vital signs    -   Complete blood count to evaluate changes in white blood cell        (WBC) count, hemoglobin and hematocrit    -   Clinical chemistry profile    -   Urinalysis (urine specific gravity, glucose, protein, ketone,        pH, blood, bilirubin, urobilinogen, nitrite, leukocytes)        Statistical Methods:

Continuous measurements were summarized by means of descriptivestatistics (i.e., number of observations, arithmetic mean, standarddeviation [SD], minimum, median, maximum). Categorical variables weresummarized by means of frequency tables (i.e. count and percentages).All baseline corrected PK parameters were tested regardingbioequivalence (ANOVA).

Summary—Conclusions

The 18 treated subjects were aged between 27 and 44. All 6 subjects insequence group A completed the study as scheduled. In sequence group B,4 out of 6 subjects and sequence group C, 5 out of 6 subjects completedthe study as scheduled.

Pharmacokinetic Conclusion:

Administration of TBS-1 under asymptomatic, symptomatic and symptomaticbut treated conditions of allergic rhinitis demonstrated a reliableincrease in testosterone serum concentrations in all three treatmentgroups. The drug induced exposure to testosterone and DHT, determined asAUC_(0-24,bc) was higher in the asymptomatic state compared tosymptomatic and symptomatic but treated state. ANOVA analysis failed todemonstrate bioequivalence between the asymptomatic state and eithersymptomatic or symptomatic but treated state.

A comparison of the AUC_(bc) over 0-24 h between symptomatic andsymptomatic but treated state revealed no bioequivalence between thesetwo treatment conditions.

However, given that the point estimates were close to 1 (1.0903 fortestosterone and 0.9944 for DHT) the failure to show bioequivalence maybe due to large inter-individual variations. These large variations ledto wide confidence intervals, which exceed the threshold values forbioequivalence of 0.8 to 1.25.

While TBS-1 bioavailability during the symptomatic state of allergicrhinitis is lower than during the asymptomatic state, the post-doseconcentrations of testosterone still demonstrate a reliable increase inlevels as compared to baseline. The relative decrease in bioavailabilityof TBS-1 under symptomatic seasonal rhinitis is not either amelioratedor aggravated by the administration of oxymetazoline.

Safety Conclusion:

TBS-1 was well tolerated. All reported AEs were of mild or moderateintensity and all were transient. All reported AEs were deemed treatmentemergent with no causality to TBS-1. Physical examination, vital signsand clinical laboratory results did not reveal any clinicallysignificant finding.

Example 16 An Open Label, Randomized, Balanced, Three Treatments,Parallel Design, Pharmacokinetic Study of Intra-Nasal TBS-1Administration to Hypogonadal Men Pharmacokinetic Simulation Report

See Exhibit D (the contents of which are incorporated herein byreference).

It should be understood that the present invention contemplates anyeffective pharmacokinetic parameter for the intra-nasal TBS-1 gels ofthe present invention, including those that may vary as much as about±25% of the pharmacokinetic parameters set forth in Exhibit D.Preferably, the present invention contemplates pharmacokineticparameters for the intra-nasal TBS-1 gels that are about 25% greaterand/or about 20% lesser than those pharmacokinetic parameters set forthin Exhibit D.

Example 17 Stability Intra Nasal Testosterone Gels and Diffusion Rates

The present invention also contemplates stable intranasal TBS-1testosterone gels as set forth in Exhibits F, G, H, I, J, K1, K2, L, M1,M2 and M3 (the contents of which are incorporated herein by reference)and intranasal TBS-1 testosterone gels having diffusion rates as setforth in Exhibit N (the contents of which are incorporated herein byreference).

Example 18 A Randomized 3-Way Cross Over Study to Assess the RelativeBioavailability, Safety and Tolerability of 4.5% TBS-1 when Administeredto Male Subjects with Seasonal Allergic Rhinitis

Amount (% w/w) Component 4.5% TBS-1 Testosterone  4.5% Castor Oil, USP87.5% Oleoyl polyoxylglycerides, Ph Eur/NF  4.0% Colloidal silicondioxide, NF  4.0%

Composition of TBS-1

This study assessed the relative bioavailability, safety andtolerability of 4.5% TBS-1 when administered to patients withsymptomatic untreated and treated (oxymetazoline) seasonal allergicrhinitis as well as asymptomatic subjects using an environmentalchallenge chamber (ECC) model.

The purpose of this study was to determine effect of allergic rhinitisand the treatment of allergic rhinitis, oxymetazoline, on the absorptionof TBS-1. This was achieved by determining the testosteronepharmacokinetic profile following administration of 11 mg TBS-1 (4.5%)three times a day in subjects that suffer from seasonal allergicrhinitis, while in the symptomatic, symptomatic but treated (withOxymetazoline) and asymptomatic states. The secondary objective of thestudy was to determine the local and systemic safety and tolerability,following three administrations of TBS-1 in subjects with seasonalallergic rhinitis and while taking oxymetazoline.

Symptoms of allergic rhinitis were induced in 18 male patients usingallergen challenge with Dactylis glomerate pollen in and EnvironmentalChallenge Chamber. The study was a 3-period cross over design in whichall subjects received each of the following treatments:

A: TBS-1 (Symptomatic State)

Symptoms of allergic rhinitis were induced in men with seasonal allergicrhinitis by exposing them to pollen of Dactylis glomerate in anenvironmental challenge chamber (ECC) prior to each administration ofTBS-1.

B: TBS-1 and Oxymetazoline (Symptomatic and Treated)

Oxymetazoline nasal spray was administered 30 minutes prior to the 0700hr dose of TBS-1 and again 12 hrs after the first dose. Symptoms ofallergic rhinitis were induced in men with seasonal allergic rhinitis byexposing them to pollen in an Environmental Challenge Chamber.

C: TBS-1 (Asymptomatic State)

TBS-1 was administered 3 times a day to men in the asymptomatic state.

This is a single site study with a planned enrolment of 18 healthy men.A 24 hour pharmacokinetic profile of testosterone and DHT will beperformed on all subjects in all treatments.

Safety Results

Eighteen (18) healthy men with allergic rhinitis were exposed to TBS-1.TBS-1 was well tolerated by subjects. There were no deaths in the studyand none of the subjects experienced any SAEs. Fifteen (15) adverseevents were encountered in the study: 2 in asymptomatic state; 6 in thesymptomatic state; and 7 in the symptomatic but treated state. None ofthe adverse events were considered related to the study drug. All eventswere of mild to moderate severity. None of the subjects werediscontinued from the treatment because of an AE (see results in thefollowing table).

TABLE Adverse Events Unrelated to TBS-1 Symptomatic AsymptomaticSymptomatic but treated State state state Event (n = 18) (n = 15) (n =17) Musculoskeletal and connective tissue disorder Musculosketal 1(5.6%) stiffness Respiratory, thoracic and mediastinal disorderEpistaxis 1 (6.7%) Dysphonia 1 (6.7%) 2 (11.8%) Oropharyngeal pain 1(6.7%) Rhinitis allergic 1 (6.7%) Invesigations Forced expiry volume 1(6.7%) 1 (5.9%) decreased General disorders and administration sitecondition Injection site phlebitis 2 (13.3%) 1 (5.9%) Infections andinfestations Nasopharyngitis 2 (11.8%) Nervous system disordersDizziness 1 (5.9%)

Test results are also presented in Exhibit M (the contents of which areincorporated herein by reference).

Example 19 A Randomized 3 Way Cross Over Study to Assess RelativeBioavailability, Safety and Tolerability of 4.5% TBS 1TBS-1 (4.5%) whenAdministered to Male Subjects with Seasonal Allergic Rhinitis inSymptomatic, Symptomatic but Treated (Oxymetazoline) and AsymptomaticStates

An environmental challenge chamber (ECC) model was used in this study.

Objectives:

The primary objective of this study was to determine and compare thepharmacokinetic (PK) profile of 11 mg TBS-1 (4.5%) administeredintranasally 3 times a day in subjects who suffered from seasonalallergic rhinitis, whilst they were in the symptomatic, symptomatic buttreated (with oxymetazoline) and asymptomatic states.

The secondary objective of this study was to determine and compare thelocal and systemic safety and tolerability, following 3 administrationsof TBS-1 in subjects with seasonal allergic rhinitis, whilst they werein the above states.

General Study Design:

The chosen cross over design allows to control for non-treatment effectssuch as period and sequence. Intra-individual measurements allow todetect treatment effects with a higher sensitivity as compared tointer-individual measurements based on smaller intra-individualvariation.

This was an open-label study, as the physical differences in theintranasal dosing devices prevent blinding. Since pharmacokineticparameters are objective measures, they were likely not affected by theopen-label design of the study.

Methodology:

This study was an open-label, balanced, randomized 3-way crossover,three-group, three-treatment, three-period pharmacokinetic study.Otherwise healthy male human subjects within the age range of 18 to 45years with seasonal allergic rhinitis in an asymptomatic state wererandomized to 1 of 3 sequence groups (A, B and C).

Subjects in sequence group A received treatment 1 in period I, treatment2 in period II and treatment 3 in period III. Subjects in sequence groupB received treatment 2 in period I and treatment 3 in period II andtreatment 1 in period III. Subjects in sequence group C receivedtreatment 3 in period I, treatment 1 in period II and treatment 2 inperiod III (as shown in the following table).

Treatments in the Three Dose Sequences PERIOD I PERIOD II PERIOD IIIVisit 3 Visit 4 Visit 5 Time 04:00-07:00 04:00-07:00 04:00-07:00 (+1day) (+1 day) (+1 Day) Sequence group A Treatment 1 Treatment 2Treatment 3 Sequence group B Treatment 2 Treatment 3 Treatment 1Sequence group C Treatment 3 Treatment 1 Treatment 2

Subjects randomized to Treatment 1 (asymptomatic state) entered the ECCand were exposed to Dactylis glomerata pollen prior to eachadministration of TBS-1. Treatment 2 was administered to subjects whowere in the symptomatic state of their diagnosed seasonal allergicrhinitis and were treated with oxymetazoline 30 min prior to the 07:00 hdose of TBS-1 and 12 hours after the first administration. Subjects wereexposed to Dactylis glomerata pollen in the ECC prior to each TBS-1administration. Subjects receiving Treatment 3 were to be in theasymptomatic state (<3 for TNSS and <2 for the congestion score) andreceived three doses of TBS-1.

Number of Subjects: 18

-   -   Safety Set:    -   Full PK population: 18    -   PK population for Bioequivalence: 14        Subject Population:

A male subject population with a history of seasonal allergic rhinitis,aged 18-45 years was chosen for this study in order to investigate theeffect of allergic rhinitis on the absorption of TBS-1 in anasymptomatic, symptomatic and symptomatic but treated state.

Diagnosis criteria: otherwise healthy male human subjects with seasonalallergic rhinitis in asymptomatic state.

Main Inclusion Criteria:

-   -   1. Otherwise healthy male human subjects within the age range of        18 to 45 years inclusive with seasonal allergic rhinitis in        asymptomatic state, which was defined by a positive case history        and a positive skin prick and/or intradermal test for Dactylis        glomerate pollen allergen within 12 months of screening.    -   2. Total Nasal Symptom Score (TNSS) of ≥6/12 and a congestion        score of ≥⅔ on at least one card during the 2-hour screening        challenge.    -   3. Willingness to provide written informed consent to        participate in the study.    -   4. Body-mass index of 30 kg/m².    -   5. Absence of significant disease or clinically significant (cs)        abnormal laboratory values on laboratory evaluations, medical        history or physical examination during screening.    -   6. Otorhinolaryngological examination without clinically        significant abnormal findings within 4 weeks of screening.    -   7. Non-smokers or ex-smokers for at least six months.    -   8. Comprehension of the nature and purpose of the study and        compliance with the requirement of the protocol.    -   Study drug: Intranasal testosterone gel (TBS-1)    -   Form and description: Multiple-dose dispenser    -   Unit strength: 5.5 mg of 4.5% testosterone gel    -   Daily dose: 33.0 mg of 4.5% testosterone gel    -   Route of administration: intranasal    -   Posology: t.i.d.    -   Batch number: 2372    -   Study drug: Oxymetazoline (Nasivin® ohne    -   Konservierungsstoffe)    -   Form and description: Multiple-dose dispenser    -   Unit strength: 0.05% oxymetazoline hydrochloride    -   Daily dose: 4 puffs (2 per nostril) of 5.05% oxymetazoline    -   hydrochloride    -   Route of administration: Intranasal    -   Posology: 30 min prior to the 07:00 h dose of TBS-1 and 12 h    -   after the first dose (during Treatment Sequence 3)    -   Study drug: Dactylis glomerata (pollen)    -   Form and description: Challenge substance for pollen chamber    -   Unit strength: 6 g    -   Daily dose: 4000±500 of Dactylis glomerata pollen    -   Route of administration: Inhalation    -   Study Period: 5 Weeks        Criteria for Evaluation:

Primary Endpoint (Pharmakokinetics):

The following pharmacokinetic (PK) parameters were determined for allsubjects in all treatments: Area under the serum concentration time plotup to 24 h (AUC₀₋₂₄), the average of the observed concentration oftestosterone and DHT in the 24 h interval (C_(avg)), minimum observedconcentration of testosterone and DHT (C_(min)), maximum observedconcentration of testosterone and DHT (C_(max)), and time of maximumobserved concentration testosterone and DHT (t_(max)) for 3 treatmentphases (Treatments 1-3).

The relative PK profiles of the 3 treatments were determined usingAUC₀₋₂₄ and C_(max) corrected for the serum testosterone concentration.

Secondary Endpoint (Safety):

Safety and tolerability were assessed by monitoring:

-   -   Adverse events    -   Otolaryngological examination    -   Vital signs    -   Complete blood count to evaluate changes in white blood cell        (WBC) count, hemoglobin and hematocrit    -   Clinical chemistry profile    -   Urinalysis (urine specific gravity, glucose, protein, ketone,        pH, blood, bilirubin, urobilinogen, nitrite, leukocytes)        Statistical Methods:

Continuous measurements were summarized by means of descriptivestatistics (i.e., number of observations, arithmetic mean, standarddeviation [SD], minimum, median, maximum). Categorical variables weresummarized by means of frequency tables (i.e. count and percentages).All baseline corrected PK parameters were tested regardingbioequivalence (ANOVA).

Subjects participating in this study were at risk for the side effectscommon to all formulations of testosterone. In addition to risksinherent to all testosterone administration, subjects receiving TBS-1 inprior clinical studies have experienced mild nasal symptoms includingdryness, inflammation, congestion, and discomfort. None of these AEsprevented subjects from continuing the medication.

The exposure to pollen in order to induce symptoms of allergic rhinitiswas associated with a minimal risk of anaphylactic reactions. Allergenchallenges with Dactylis glomerate pollen in the Fraunhofer ECC weredesigned to mimic the situation for the subject under quasi-naturalconditions. Therefore, the pollen exposure in the ECC did not present agreater risk than natural exposure during the grass pollen season insummer. The experimental setting was validated and used in numerousclinical trials. Inhalation of pollen can cause bronchoconstriction inasthmatic subjects. However, asthmatic subjects were excluded from thestudy. For risk minimization measures with respect to pollen challenge.

Subjects receiving oxymetazoline (Nasivin©) were at risk of thedescribed side-effects of this product. Frequent side-effects areburning and dryness of the nasal mucosa and sneezing. Uncommon sideeffects are agitation, fatigue, headache, hallucinations (mainlyobserved in children), tachycardia, hypertension, arrhythmia, nosebleeding, convulsions (mainly observed in children) and hypersensitivityreactions, such as, itching and rash. However, since each subjectreceived only 2 doses of oxymetazoline, the risk of developingside-effects was minimal.

Testosterone replacement therapy for hypogonadal men should correct theclinical abnormalities of testosterone deficiency. Since this was aPhase I study enrolling men not suffering from hypogonadism between theages of 18-45 years it was not anticipated that these volunteers woulddirectly benefit by taking part in this study.

Conclusions

The 18 treated subjects were aged between 27 and 44. All 6 subjects insequence group A completed the study as scheduled. In sequence group B,4 out of 6 subjects and sequence group C, 5 out of 6 subjects completedthe study as scheduled.

Pharmacokinetic Conclusion:

Administration of TBS-1 under asymptomatic, symptomatic and symptomaticbut treated conditions of allergic rhinitis demonstrated a reliableincrease in testosterone serum concentrations in all three treatmentgroups. The drug induced exposure to testosterone and DHT, determined asAUC_(0-24,bc) was higher in the asymptomatic state compared tosymptomatic and symptomatic but treated state. ANOVA analysis failed todemonstrate bioequivalence between the asymptomatic state and eithersymptomatic or symptomatic but treated state.

A comparison of the AUC_(bc) over 0-24 h between symptomatic andsymptomatic but treated state revealed no bioequivalence between thesetwo treatment conditions. However, given that the point estimates wereclose to 1 (1.0903 for testosterone and 0.9944 for DHT) the failure toshow bioequivalence may be due to large inter-individual variations.These large variations led to wide confidence intervals, which exceedthe threshold values for bioequivalence of 0.8 to 1.25.

Administration of 4.5% TBS-1 under asymptomatic, symptomatic andsymptomatic but treated conditions of allergic rhinitis demonstrated areliable increase in testosterone serum concentrations under all threetreatment conditions. 4.5% TBS 1 bioavailability during the symptomaticstate of allergic rhinitis was 21% lower compared to the asymptomaticstate, based on AUC0-24 values.

While TBS-1 bioavailability during the symptomatic state of allergicrhinitis is lower than during the asymptomatic state, the post-doseconcentrations of testosterone still demonstrate a reliable increase inlevels as compared to baseline. The relative decrease in bioavailabilityof 4.5% TBS 1 under symptomatic seasonal rhinitis was neitherameliorated nor aggravated by the administration of oxymetazoline.

Safety Conclusion:

TBS-1 was well tolerated. All reported AEs were of mild or moderateintensity and all were transient. All reported AEs were deemed treatmentemergent with no causality to TBS-1. Physical examination, vital signsand clinical laboratory results did not reveal any clinicallysignificant finding.

See FIGS. 44 and 45 respectively

Example 20 Drug-Drug Interaction Study to Evaluate Administration Routeof Intranasal Application of Testosterone and to Investigate PotentialInteraction of Testosterone with a Nasal Decongestant Spray

A drug-drug Interaction study was completed, which was an extrinsicfactor study to evaluate whether intranasal application of testosteroneis a reliable route of administration during naturally occurring nasalinflammation such as allergic rhinitis and to investigate the potentialinteraction of TBS-1 with a nasal decongestant spray, oxymetazoline. Thestudy was conducted at one site in Germany.

Treatment Regimen.

Subjects were randomly assigned to a treatment sequence comprised ofTBS-1 when they were asymptomatic, symptomatic and untreated andsymptomatic and treated with oxymetazoline nasal spray. The symptomaticstate was induced by exposure to Dactylis glomerata pollen in anenvironment exposure chamber (EEC).

The symptomatic state was defined by a positive case history, a positiveskin prick and/or interdermal test for Dactylis glomerata allergen and aTotal nasal Symptom Score (TNSS) of ≥6/12 and a congestion score of ≥⅔.TBS-1 administration to subjects in a symptomatic and treated armreceived oxymetazoline 30 minutes prior to the 07:00 hour dose of TBS 1and 12 hours after the first administration. All patients received 3doses of TBS-1 at 07:00, 13:00 and 21:00 hrs.

Primary Objective

The primary objective of this study was to determine and compare thepharmacokinetic (PK) profile of 11 mg TBS-1 (4.5%) administeredintranasally 3 times a day in subjects who suffered from seasonalallergic rhinitis, whilst they were in the symptomatic, symptomatic buttreated (with oxymetazoline) and asymptomatic states.

Subject Disposition

The 18 treated subjects were healthy subjects with seasonal allergicrhinitis aged between 27 and 44. All 6 subjects in sequence group Acompleted the study as scheduled. In sequence group B, 4 out of 6subjects and sequence group C, 5 out of 6 subjects completed the studyas scheduled. In total, the number of subjects completing each of the 3states were: asymptomatic (N=18), symptomatic but treated (N=17), andsymptomatic untreated (N=15).

Analysis of Primary Endpoint

Administration of TBS-1 under asymptomatic, symptomatic and symptomaticbut treated conditions of allergic rhinitis demonstrated a reliableincrease in testosterone serum concentrations under all 3 treatmentconditions as presented in the following table and the following figure.

TABLE AUC Values for Serum Testosterone by Treatment Condition IncludingNon-Corrected Values, Corrected Values and Pre-dose Corrected ValuesPre-dose Non-corrected Corrected Corrected Values Values* Values^(#)Asymptomatic 16746 ± 3894 5797 ± 2643 3841 ± 2713 Symptomatic 13217 ±3589 2267 ± 2172 3041 ± 1967 Symptomatic but 12778 ± 3379 1828 ± 18893138 ± 1480 treated *Corrected values = uncorrected values-baseline 24hour ^(#)Pre-dose corrected values = PK values were corrected fortreatment specific pre-dose levelsSee FIG. 46 .

FI Serum Testosterone (ng/dL): Arithmetic Mean Concentration vs. TimeCurve, Linear Scale (PK set)

The testosterone exposure as estimated by the mean baseline-correctedarea under the serum concentration-time curve from 0 to 24 hourspost-dose AUC_(0-24,bc) was higher for subjects in the asymptomaticstate compared to symptomatic and symptomatic but treated state. Ananalysis of variance did not demonstrate bioequivalence between theasymptomatic state and either symptomatic and symptomatic but treatedstate.

The difference in AUC_(0-24,bc) between the symptomatic untreated andthe symptomatic treated states was small, indicating that administrationof oxymetazoline did not relevantly affect the absorption of TBS-1;however, they were not bioequivalent. Given that the point estimateswere close to 1 (1.0903) the failure to show bioequivalence may be dueto large interindividual variations. These large variations led to wideconfidence intervals, which exceed the threshold for bioequivalence of0.8 to 1.25.

TBS 1 bioavailability during the symptomatic state of allergic rhinitiswas 21% lower compared the asymptomatic state, based on AUC₀₋₂₄ values.However, the post-dose concentrations of testosterone still demonstratea reliable increase in levels as compared to baseline. The relativedecrease in bioavailability of TBS-1 under symptomatic seasonal rhinitisis neither ameliorated nor aggravated by the administration ofoxymetazoline.

Additional exploratory analysis revealed that the different treatmentconditions influenced the pre-dose value of testosterone. A studentt-test showed significant differences in the pre-dose testosteronebetween the asymptomatic treatment condition compared to the symptomaticand the symptomatic and treated conditions. Subjects were exposed to anEEC in the symptomatic and symptomatic and treated condition but not inthe asymptomatic condition. It is hypothesized that the earlier wake uptime and/or stress caused by procedures associated with confinement inthe EEC may have led to lower testosterone values in both symptomaticstates compared to the asymptomatic state. As such, the baseline profilecollected under the EEC conditions and used for correction purposes wasnot truly representative of the non-treated state under all studyconditions. The additional analysis corrected for endogenoustestosterone by pre-dose values instead of correction by 24 hourbaseline profile. This analysis showed that the differences betweenasymptomatic and both symptomatic treatment conditions were lesspronounced with respect to AUC_(bc), C_(avg,bc), and C_(max,bc).However, bioequivalence could not be shown between treatment conditions.

REFERENCE LIST

-   1. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics,    4th edition, 2006. Editors; Burtis C A, Ashwood E R, and Bruns D E.-   2. Wang C, Swerdloff RS. Androgen replacement therapy. Ann Med 1997;    29: 365-370.-   3. Matsumoto A M. Andropause: clinical implications of the decline    in serum Testosterone levels with aging in men. J Gerontol A Med Sci    2002; 57: M76-M99.-   4. Haren M T, Kim M J, Tariq S H, Wittert G A, Morley J E.    Andropause: a quality-of-life issue in older males. Med Clin North    Am 2006; 90: 1005-1023.-   5. Nieschlag E. Testosterone treatment comes of age: new options for    hypogonadal men. Clin Endocrinol (Oxf) 2006: 65: 275-281.-   6. Tenover J L. The androgen-deficient aging male: current treatment    options. Rev Urol 2003; 5 (Suppl): S22-S28.-   7. Jockenhovel F. Testosterone therapy—what, when and to whom? Aging    Male 2004; 7: 319-324.-   8. Kunz G H, Klein K O, Clemons R D, Gottschalk M E, Jones K L.    Virilization of young children after topical androgen use by their    parents. Pediatrics 2004; 114: 282-284.-   9. Brachet C, Vermeulen J, Heinrichs C. Children's virilisation and    the use of a Testosterone gel by their fathers. Eur J Pediatr 2005;    164: 646-647.-   10. Bagchus W M, Hust R, Maris F, Schnabel P G, Houwing N S.    Important effect of food on the bioavailability of oral Testosterone    undecanoate. Pharmacotherapy 2003; 23: 319-325.-   11. Haren M, Chapman I M, Haren M T, MacKintosh S, Coates P, Morley    J E. Oral Testosterone supplementation increases muscle and    decreases fat mass in healthy elderly males with low normal gonadal    status. J Gerontol A Biol Sci Med Sci 2003; 58: 618-625.-   12. Haren M, Chapman I, Coates P, Morley J E, Wittert G. Effect of    12 month oral Testosterone on Testosterone deficiency symptoms in    symptomatic elderly males with low-normal gonadal status. Age Ageing    2005; 34: 123-130.-   13. Mattern C, Hoffmann C, Morley J E, Badiu C. The Aging Male 2008;    11: 171-178.

What is claimed is:
 1. A method of treating a male, who is experiencingsymptomatic allergic or seasonal rhinitis, with testosterone replacementtherapy for a condition associated with a deficiency or absence ofendogenous testosterone who is in need of such testosterone replacementtreatment, the method comprising: administering intranasally to thesymptomatic male three times a day an intranasal testosterone gel todeliver intranasally to the symptomatic male a total daily dose of about33 mg of testosterone to effectively treat said condition in thesymptomatic male wherein said condition is hypogonadism; and providing ametered dose pump containing 11 grams of the intranasal testosteronegel, wherein the metered dose pump dispenses 60 metered pump actuations,wherein one pump actuation delivers 5.5 mg of the testosterone in 0.122grams of the intranasal testosterone gel, so that, when the symptomaticmale actuates the one said pump from the metered dose pump into eachnostril of the symptomatic male three times a day, the total daily doseof about 33 mg of testosterone is intranasally administered to thesymptomatic male.
 2. An intranasal testosterone method for treating amale, who is symptomatic for allergic or seasonal rhinitis, withtestosterone replacement therapy for a condition associated with adeficiency or absence of endogenous testosterone that is in need of suchtestosterone replacement treatment, said method comprising: providing ametered dose pump containing 11 grams of an intranasal testosterone gel,wherein the metered dose pump dispenses 60 metered pump actuations ofthe intranasal testosterone gel; and instructing the symptomatic male toactuate one pump from the metered dose pump into each nostril of thesymptomatic male three times a day to deliver intranasally to thesymptomatic male a total daily dose of about 33 mg of testosterone toeffectively treat the symptomatic male for the condition; wherein theone pump actuation delivers 5.5 mg of the testosterone in 0.122 grams ofthe intranasal testosterone gel into each of the nostrils; wherein thecondition is hypogonadism; and wherein the hypogonadism is selected froma group of hypogonadisms consisting of congenital or acquired primaryhypogonadism and congenital or acquired hypogonadotropic hypogonadism.